Access the full text.
Sign up today, get DeepDyve free for 14 days.
Ruth Lan, T. Salunga, K. Tsuneyama, Zhe‐Xiong Lian, Guo-xiang Yang, W. Hsu, Y. Moritoki, A. Ansari, C. Kemper, J. Price, J. Atkinson, R. Coppel, M. Gershwin (2009)Hepatic IL-17 responses in human and murine primary biliary cirrhosis.
Journal of autoimmunity, 32 1
Y Kondo (2006)4310
World J Gastroenterol, 12
Xiaohui Zhang, Min Feng, Xin Liu, L. Bai, M. Kong, Yu Chen, S. Zheng, Shuang Liu, Y. Wan, Z. Duan, Yuanping Han (2016)Persistence of cirrhosis is maintained by intrahepatic regulatory T cells that inhibit fibrosis resolution by regulating the balance of tissue inhibitors of metalloproteinases and matrix metalloproteinases.
Translational research : the journal of laboratory and clinical medicine, 169
R Bataller (2012)14293
Proc Natl Acad Sci USA, 109
Jun-ichi Nunoya, Michael Washburn, G. Kovalev, L. Su (2014)Regulatory T cells prevent liver fibrosis during HIV type 1 infection in a humanized mouse model.
The Journal of infectious diseases, 209 7
Hui-Chuan Sun, Jiming Zhang, H. Zhang, Z. Zou, F. Wang, J. Jia (2012)Increased Th17 cells contribute to disease progression in patients with HBV‐associated liver cirrhosis
Journal of Viral Hepatitis, 19
X Zhang (2016)67
Transl Res, 169
David Botta, M. Fuller, T. Marquez-Lago, Holly Bachus, J. Bradley, A. Weinmann, A. Zajac, T. Randall, F. Lund, B. León, A. Ballesteros-Tato (2017)Dynamic regulation of T Follicular Regulatory cell responses by interleukin 2 during influenza infection
Nature immunology, 18
Minjie Wan, Jiawen Han, Lili Ding, F. Hu, P. Gao (2021)Novel Immune Subsets and Related Cytokines: Emerging Players in the Progression of Liver Fibrosis
Frontiers in Medicine, 8
M. Claassen, R. Knegt, H. Tilanus, H. Janssen, A. Boonstra (2010)Abundant numbers of regulatory T cells localize to the liver of chronic hepatitis C infected patients and limit the extent of fibrosis.
Journal of hepatology, 52 3
Y Koyama (2017)55
J Clin Investig, 127
H. Louis, J. Laethem, Wei Wu, E. Quertinmont, C. Degraef, K. Berg, A. Demols, M. Goldman, O. Moine, A. Geerts, J. Devière (1998)Interleukin‐10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice
R Bataller (2005)209
J Clin Investig, 115
Y. Choi, Jeewon Lee, H. Lee, D. Chang, P. Sung, M. Jung, J. Park, J. Kim, J. Lee, Hana Park, J. Cheong, K. Suh, Hyung Kim, June-Sung Lee, Kyung-Ah Kim, E. Shin (2014)Liver injury in acute hepatitis A is associated with decreased frequency of regulatory T cells caused by Fas-mediated apoptosis
R. Gershon, K. Kondo (1970)Cell interactions in the induction of tolerance: the role of thymic lymphocytes.
Immunology, 18 5
M. Iman, R. Rezaei, Sadegh Jamalkandi, P. Shariati, F. Kheradmand, J. Salimian (2017)Th17/Treg immunoregulation and implications in treatment of sulfur mustard gas-induced lung diseases
Expert Review of Clinical Immunology, 13
Takuma Tsuchida, S. Friedman (2017)Mechanisms of hepatic stellate cell activation
Nature Reviews Gastroenterology &Hepatology, 14
J Li (2012)e39307
PloS One, 7
T. Mangodt, M. Herck, S. Nullens, J. Ramet, J. Dooy, P. Jorens, B. Winter (2015)The role of Th17 and Treg responses in the pathogenesis of RSV infection
Pediatric Research, 78
Zhongqi Liu, Kun-Peng Wang, Ji-lin Ma, S. Zheng (2015)The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells
Cellular and Molecular Immunology, 12
Liyun Wang, Shijun Chen, Keshu Xu (2011)IL-17 expression is correlated with hepatitis B‑related liver diseases and fibrosis.
International journal of molecular medicine, 27 3
M Ito (2019)246
L Gu (2016)1153
Mol Med Rep., 14
Xiaohui Zhang, J. Lou, L. Bai, Yu Chen, S. Zheng, Z. Duan (2017)Immune Regulation of Intrahepatic Regulatory T Cells in Fibrotic Livers of Mice
Medical Science Monitor : International Medical Journal of Experimental and Clinical Research, 23
Jing Li, S. Qiu, Wei‐Min She, Fu-ping Wang, Hong Gao, Lei Li, Chuan-Tao Tu, Ji‐yao Wang, X. Shen, Wei Jiang (2012)Significance of the Balance between Regulatory T (Treg) and T Helper 17 (Th17) Cells during Hepatitis B Virus Related Liver Fibrosis
PLoS ONE, 7
Y. Roh, Surim Park, C. Lim, Bumseok Kim (2015)Depletion of Foxp3+ Regulatory T Cells Promotes Profibrogenic Milieu of Cholestasis-Induced Liver Injury
Digestive Diseases and Sciences, 60
GL Davis (2003)331
Liver Transpl., 9
S Hemmann (2007)955
J Hepatol, 46
Y Kondo (2015)3307
Int J Mol Sci, 16
S. Hemmann, J. Graf, M. Roderfeld, E. Roeb (2007)Expression of MMPs and TIMPs in liver fibrosis - a systematic review with special emphasis on anti-fibrotic strategies.
Journal of hepatology, 46 5
Y Ikeno (2020)584048
Front Immunol, 11
Yuanyuan Xie, Shuo Liu, Liudi Wang, Huizhen Yang, Chenxu Tai, Li Ling, Libo Chen, Shanshan Liu, Bin Wang (2021)Individual heterogeneity screened umbilical cord-derived mesenchymal stromal cells with high Treg promotion demonstrate improved recovery of mouse liver fibrosis
Stem Cell Research & Therapy, 12
Wenhong Wang, S. Shao, Z. Jiao, M. Guo, Huaxi Xu, Shengjun Wang (2012)The Th17/Treg imbalance and cytokine environment in peripheral blood of patients with rheumatoid arthritis
Rheumatology International, 32
S. Duarte, J. Baber, T. Fujii, A. Coito (2015)Matrix metalloproteinases in liver injury, repair and fibrosis
Matrix biology : journal of the International Society for Matrix Biology, 0
B. Langhans, Abdel Alwan, B. Krämer, A. Glässner, P. Lutz, C. Strassburg, J. Nattermann, U. Spengler (2015)Regulatory CD4+ T cells modulate the interaction between NK cells and hepatic stellate cells by acting on either cell type.
Journal of hepatology, 62 2
Chaoqi Zhang, Lifeng Li, Kexin Feng, Daoyang Fan, W. Xue, Jingli Lu (2017)‘Repair’ Treg Cells in Tissue Injury
Cellular Physiology and Biochemistry, 43
LA Ormandy (2005)2457
Cancer Res, 65
N. Ohkura, S. Sakaguchi (2020)Transcriptional and epigenetic basis of Treg cell development and function: its genetic anomalies or variations in autoimmune diseases
Cell Research, 30
N Ohkura (2020)465
Cell Res, 30
S. Katz, Kristin Ryan, N. Ahmed, G. Plitas, Umer Chaudhry, T. Kingham, Seema Naheed, Cang Nguyen, P. Somasundar, N. Espat, R. Junghans, R. DeMatteo (2011)Obstructive Jaundice Expands Intrahepatic Regulatory T Cells, Which Impair Liver T Lymphocyte Function but Modulate Liver Cholestasis and Fibrosis
The Journal of Immunology, 187
Minako Ito, Kyoko Komai, S. Mise-Omata, Mana Iizuka-Koga, Y. Noguchi, T. Kondo, R. Sakai, K. Matsuo, T. Nakayama, O. Yoshie, Hiroko Nakatsukasa, S. Chikuma, T. Shichita, A. Yoshimura (2019)Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery
W. Zhou, Yingying Yang, C. Mei, Panpan Dong, S. Mu, Hongchu Wu, Yonghua Zhou, Yi Zheng, F. Guo, Jun-Qi Yang (2019)Inhibition of Rho-Kinase Downregulates Th17 Cells and Ameliorates Hepatic Fibrosis by Schistosoma japonicum Infection
CJ Albany (2019)2795
Front Immunol, 10
M Wan (2021)604894
Front Med, 8
D Botta (2017)1249
Nat Immunol, 18
Lars Ormandy, Tina Hillemann, H. Wedemeyer, M. Manns, T. Greten, F. Korangy (2005)Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma.
Cancer research, 65 6
T Kisseleva (2021)151
Nat Rev Gastroenterol Hepatol, 18
J Nunoya (2014)1039
J Infect Dis, 209
J. Shan, Hong Jin, Yan Xu (2020)T Cell Metabolism: A New Perspective on Th17/Treg Cell Imbalance in Systemic Lupus Erythematosus
Frontiers in Immunology, 11
T Tsuchida (2017)397
Nat Rev Gastroenterol Hepatol, 14
S Kordasti (2016)1193
R. Cabrera, Z. Tu, Yiling Xu, R. Firpi, H. Rosen, Chen Liu, D. Nelson (2004)An immunomodulatory role for CD4+CD25+ regulatory T lymphocytes in hepatitis C virus infection
Xue-Ping Nan, Ye Zhang, Hai-tao Yu, Ruihao Sun, Mei-Juan Peng, Y. Li, W. Su, J. Lian, Jiu-ping Wang, X. Bai (2012)Inhibition of viral replication downregulates CD4(+)CD25(high) regulatory T cells and programmed death-ligand 1 in chronic hepatitis B.
Viral immunology, 25 1
M. Fujimoto, Mayumi Nakano, F. Terabe, H. Kawahata, T. Ohkawara, Yongmei Han, B. Ripley, S. Serada, T. Nishikawa, A. Kimura, S. Nomura, T. Kishimoto, T. Naka (2011)The Influence of Excessive IL-6 Production In Vivo on the Development and Function of Foxp3+ Regulatory T Cells
The Journal of Immunology, 186
A. Taylor, Alexandra Carey, Ramesh Kudira, Celine Lages, Tiffany Shi, Simon Lam, Rebekah Karns, Julia Simmons, K. Shanmukhappa, Maha Almanan, C. Chougnet, A. Miethke (2018)Interleukin 2 Promotes Hepatic Regulatory T Cell Responses and Protects From Biliary Fibrosis in Murine Sclerosing Cholangitis
MG Roncarolo (2006)28
Immunol Rev, 212
M Feng (2012)189
Int Immunopharmacol, 12
H. Drescher, L. Bartsch, S. Weiskirchen, R. Weiskirchen (2020)Intrahepatic TH17/TReg Cells in Homeostasis and Disease—It’s All About the Balance
Frontiers in Pharmacology, 11
armen Berasaina, Matías Avilaa (2020)Amphiregulin
H Louis (1998)1607
Y. Kondo, T. Shimosegawa (2015)Significant Roles of Regulatory T Cells and Myeloid Derived Suppressor Cells in Hepatitis B Virus Persistent Infection and Hepatitis B Virus-Related HCCs
International Journal of Molecular Sciences, 16
Min Feng, Quanrongzi Wang, Feng Zhang, Ling Lu (2012)Ex vivo induced regulatory T cells regulate inflammatory response of Kupffer cells by TGF-beta and attenuate liver ischemia reperfusion injury.
International immunopharmacology, 12 1
G Jiang (2008)1492
R Cabrera (2004)1062
SL Friedman (2003)S38
J Hepatol, 38
S Sakaguchi (1995)1151
J Immunol., 155
Takeshi Takahashi, Tomoyuki Tagami, S. Yamazaki, T. Uede, J. Shimizu, N. Sakaguchi, T. Mak, S. Sakaguchi (2000)Immunologic Self-Tolerance Maintained by Cd25+Cd4+Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4
The Journal of Experimental Medicine, 192
M Miyara (2009)899
Biao Huang, Xixi Cheng, Huafeng Wang, Wen-Chiung Huang, Zha hu, Dan Wang, Kai Zhang, Huan Zhang, Zhenyi Xue, Yurong Da, Ning Zhang, Yong‐cheng Hu, Z. Yao, L. Qiao, Fei Gao, Rongxin Zhang (2016)Mesenchymal stem cells and their secreted molecules predominantly ameliorate fulminant hepatic failure and chronic liver fibrosis in mice respectively
Journal of Translational Medicine, 14
S. Friedman (2008)Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.
Physiological reviews, 88 1
J. Lunz, S. Specht, N. Murase, K. Isse, A. Demetris (2007)Gut‐derived commensal bacterial products inhibit liver dendritic cell maturation by stimulating hepatic interleukin‐6/signal transducer and activator of transcription 3 activity
C. Albany, S. Trevelin, G. Giganti, G. Lombardi, C. Scottà (2019)Getting to the Heart of the Matter: The Role of Regulatory T-Cells (Tregs) in Cardiovascular Disease (CVD) and Atherosclerosis
Frontiers in Immunology, 10
Yoshinobu Ikeno, Daiya Ohara, Yusuke Takeuchi, Hitomi Watanabe, G. Kondoh, K. Taura, S. Uemoto, K. Hirota (2020)Foxp3+ Regulatory T Cells Inhibit CCl4-Induced Liver Inflammation and Fibrosis by Regulating Tissue Cellular Immunity
Frontiers in Immunology, 11
Guangcun Huang, Jinsheng Zhang, Q. Tang (2004)Involvement of C/EBP-α gene in in vitro activation of rat hepatic stellate cells
Biochemical and Biophysical Research Communications, 324
Lanlan Yang, Shengnan Jia, Xue Shao, Siqi Liu, Qian Zhang, Jie Song, Wudong Wang, Zhenjing Jin (2019)Interleukin-35 modulates the balance between viral specific CD4+CD25+CD127dim/- regulatory T cells and T helper 17 cells in chronic hepatitis B virus infection
Virology Journal, 16
Xueping Yu, Ruyi Guo, Desong Ming, Mi-long Su, Chengzu Lin, Yong Deng, Zhenzhong Lin, Zhijun Su (2014)Ratios of regulatory T cells/T‐helper 17 cells and transforming growth factor‐β1/interleukin‐17 to be associated with the development of hepatitis B virus‐associated liver cirrhosis
Journal of Gastroenterology and Hepatology, 29
Leena Halim, M. Romano, R. McGregor, I. Correa, P. Pavlidis, Nathali Grageda, S. Hoong, M. Yuksel, W. Jassem, R. Hannen, Mark Ong, Olivia Mckinney, B. Hayee, S. Karagiannis, N. Powell, R. Lechler, E. Nova-Lamperti, G. Lombardi (2017)An Atlas of Human Regulatory T Helper-like Cells Reveals Features of Th2-like Tregs that Support a Tumorigenic Environment
Cell Reports, 20
Song Zhai, Li Zhang, S. Dang, Yong Yu, Zigang Zhao, Wenxue Zhao, Layang Liu (2011)The ratio of Th-17 to Treg cells is associated with survival of patients with acute-on-chronic hepatitis B liver failure.
Viral immunology, 24 4
G. Jiang, H. Yang, Lianfu Wang, G. Wildey, J. Fung, S. Qian, Lina Lu (2008)Hepatic Stellate Cells Preferentially Expand Allogeneic CD4+CD25+FoxP3+ Regulatory T Cells in an IL-2-Dependent Manner
J. Estes, S. Wietgrefe, T. Schacker, P. Southern, G. Beilman, C. Reilly, J. Milush, J. Lifson, D. Sodora, J. Carlis, A. Haase (2007)Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor beta 1-positive regulatory T cells and begins in early infection.
The Journal of infectious diseases, 195 4
TB Bertolini (2021)104251
Cell Immunol, 359
H. Weiner (2001)Oral tolerance: immune mechanisms and the generation of Th3-type TGF-beta-secreting regulatory cells.
Microbes and infection, 3 11
Inhibition of Rho - kinase downregulates Th 17
Xiao-fei Sun, Lei Gu, Wen-sheng Deng, Qing Xu (2014)Impaired balance of T helper 17/T regulatory cells in carbon tetrachloride-induced liver fibrosis in mice.
World journal of gastroenterology, 20 8
S Duarte (2015)147
Matrix Biol, 44-46
S Duarte, J Baber, T Fujii, AJ Coito (2015)Matrix metalloproteinases in liver injury, repair and fibrosis. Matrix biology: journal of the International Society for
Matrix Biol, 44-46
Thais Bertolini, Moanaro Biswas, C. Terhorst, H. Daniell, R. Herzog, A. Piñeros (2020)Role of orally induced regulatory T cells in immunotherapy and tolerance.
Cellular immunology, 359
G. Rong, Y. Zhou, Y. Xiong, L. Zhou, H. Geng, T. Jiang, Y. Zhu, H. Lu, S. Zhang, P. Wang, B. Zhang, R. Zhong (2009)Imbalance between T helper type 17 and T regulatory cells in patients with primary biliary cirrhosis: the serum cytokine profile and peripheral cell population
Clinical & Experimental Immunology, 156
Y. Koyama, D. Brenner (2017)Liver inflammation and fibrosis.
The Journal of clinical investigation, 127 1
Maria Roncarolo, S. Gregori, M. Battaglia, R. Bacchetta, K. Fleischhauer, M. Levings (2006)Interleukin‐10‐secreting type 1 regulatory T cells in rodents and humans
Immunological Reviews, 212
R Bataller, DA Brenner (2005)Liver fibrosis
J Clin Investig, 115
F. Deknuydt, G. Bioley, D. Valmori, M. Ayyoub (2009)IL-1beta and IL-2 convert human Treg into T(H)17 cells.
Clinical immunology, 131 2
S. Sakaguchi (2004)Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses.
Annual review of immunology, 22
L Halim (2017)757
Cell Rep., 20
G. Davis, J. Albright, S. Cook, D. Rosenberg (2003)Projecting future complications of chronic hepatitis C in the United States
Liver Transplantation, 9
T Takahashi (2000)303
J Exp Med, 192
C Zhang (2017)2155
Cell Physiol Biochem., 43
V Hernandez-Gea (2011)425
Annu Rev Pathol, 6
D. Boveda-Ruiz, C. D'Alessandro-Gabazza, M. Toda, T. Takagi, M. Naito, Y. Matsushima, Takahiro Matsumoto, Tetsu Kobayashi, P. Gil-Bernabe, Ayshwarya-Lakshmi Chelakkot-Govindalayathil, Y. Miyake, A. Yasukawa, J. Morser, O. Taguchi, E. Gabazza (2013)Differential role of regulatory T cells in early and late stages of pulmonary fibrosis.
Immunobiology, 218 2
A O’Garra (2004)801
Nat Med, 10
C Berasain, MA Avila (2014)Amphiregulin
Semin Cell Dev Biol, 28
SL Friedman (2008)125
Physiol Rev, 88
S. Sakaguchi, N. Sakaguchi, M. Asano, M. Itoh, M. Toda (1995)Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.
Journal of immunology, 155 3
Liang Zhou, M. Chong, D. Littman (2009)Plasticity of CD4+ T cell lineage differentiation.
Immunity, 30 5
HL Weiner (2011)241
Immunol Rev, 241
Yong-Ting Lan, Zhen-li Wang, P. Tian, Xiaodong Gong, Yu-Chen Fan, Kai Wang (2019)Treg/Th17 imbalance and its clinical significance in patients with hepatitis B-associated liver cirrhosis
Diagnostic Pathology, 14
B. Langhans, H. Nischalke, B. Krämer, A. Hausen, L. Dold, P. Heteren, R. Hüneburg, J. Nattermann, C. Strassburg, U. Spengler (2017)Increased peripheral CD4+ regulatory T cells persist after successful direct-acting antiviral treatment of chronic hepatitis C.
Journal of hepatology, 66 5
R. Xu, Zheng Zhang, Fu-Sheng Wang (2011)Liver fibrosis: mechanisms of immune-mediated liver injury
Cellular and Molecular Immunology, 9
T. Kisseleva, D. Brenner (2020)Molecular and cellular mechanisms of liver fibrosis and its regression
Nature Reviews Gastroenterology & Hepatology, 18
M Yuksel (2022)200
J Pediatr Gastroenterol Nutr, 74
C Berasain (2014)31
Semin Cell Dev Biol, 28
Zhe-tong Deng, Jinren Zhou, X. Mu, J. Gu, Xiangyu Li, Qing Shao, Jinyang Li, Chao Yang, Guoyong Han, Jie Zhao, Yongxiang Xia (2021)Regulatory T Cells Improved the Anti-cirrhosis Activity of Human Amniotic Mesenchymal Stem Cell in the Liver by Regulating the TGF-β-Indoleamine 2,3-Dioxygenase Signaling
Frontiers in Cell and Developmental Biology, 9
Y Ilan, R Maron, AM Tukpah, TU Maioli, G Murugaiyan, K Yang (2010)Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice
Proc Natl Acad Sci USA, 107
Lei Gu, Wen-sheng Deng, Xiao-fei Sun, Hong Zhou, Qing Xu (2016)Rapamycin ameliorates CCl4-induced liver fibrosis in mice through reciprocal regulation of the Th17/Treg cell balance
Molecular Medicine Reports, 14
Dongping Xu, Jun‐liang Fu, Lei Jin, Hui Zhang, Chun-Bao Zhou, Z. Zou, Jingmin Zhao, Bin Zhang, M. Shi, Xilai Ding, Zi-rong Tang, yang-xin fu, Fu-Sheng Wang (2006)Circulating and Liver Resident CD4+CD25+ Regulatory T Cells Actively Influence the Antiviral Immune Response and Disease Progression in Patients with Hepatitis B1
The Journal of Immunology, 177
S. Friedman (2003)Liver fibrosis -- from bench to bedside.
Journal of hepatology, 38 Suppl 1
MA Claassen (2010)315
J Hepatol, 52
A. O’Garra, P. Vieira (2004)Regulatory T cells and mechanisms of immune system control
Nature Medicine, 10
A. Silini, M. Magatti, A. Cargnoni, O. Parolini (2017)Is Immune Modulation the Mechanism Underlying the Beneficial Effects of Amniotic Cells and Their Derivatives in Regenerative Medicine?
Cell Transplantation, 26
B. Langhans, B. Krämer, M. Louis, H. Nischalke, R. Hüneburg, A. Staratschek‐Jox, M. Odenthal, S. Manekeller, M. Schepke, J. Kalff, H. Fischer, J. Schultze, U. Spengler (2013)Intrahepatic IL-8 producing Foxp3⁺CD4⁺ regulatory T cells and fibrogenesis in chronic hepatitis C.
Journal of hepatology, 59 2
J. Nono, M. Lutz, K. Brehm (2020)Expansion of Host Regulatory T Cells by Secreted Products of the Tapeworm Echinococcus multilocularis
Frontiers in Immunology, 11
M. Miyara, Y. Yoshioka, A. Kitoh, T. Shima, K. Wing, A. Niwa, C. Parizot, C. Taflin, T. Heike, D. Valeyre, A. Mathian, T. Nakahata, Tomoyuki Yamaguchi, T. Nomura, M. Ono, Z. Amoura, G. Gorochov, S. Sakaguchi (2009)Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor.
Immunity, 30 6
V. Hernández-Gea, S. Friedman (2011)Pathogenesis of liver fibrosis.
Annual review of pathology, 6
M Iman (2017)1173
Expert Rev Clin Immunol, 13
J. Ladero (2011)Noninvasive Evaluation of Liver Fibrosis in Patients with Chronic Hepatitis C
Hepatitis Monthly, 11
Y. Kondo, Koju Kobayashi, Y. Ueno, M. Shiina, H. Niitsuma, N. Kanno, Tomoo Kobayashi, T. Shimosegawa (2006)Mechanism of T cell hyporesponsiveness to HBcAg is associated with regulatory T cells in chronic hepatitis B.
World journal of gastroenterology, 12 27
S Sakaguchi (2004)531
Annu Rev Immunol, 22
R Bataller, SM Lemon (2012)Fueling fibrosis in chronic hepatitis C
Proc Natl Acad Sci USA, 109
S. Kordasti, B. Costantini, T. Seidl, P. Abellan, M. Llordella, D. McLornan, K. Diggins, A. Kulasekararaj, C. Benfatto, X. Feng, A. Smith, S. Mian, R. Melchiotti, E. Rinaldis, R. Ellis, N. Petrov, G. Povoleri, S. Chung, N. Thomas, F. Farzaneh, J. Irish, S. Heck, N. Young, J. Marsh, G. Mufti (2016)Deep phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment.
Blood, 128 9
Z. Tan, X. Qian, R. Jiang, Qianghui Liu, Youjing Wang, Chen Chen, Xuehao Wang, B. Ryffel, Beicheng Sun (2013)IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation
The Journal of Immunology, 191
B Langhans (2015)398
J Hepatol, 62
Fanli Meng, Kai Wang, Tomonori Aoyama, S. Grivennikov, Y. Paik, D. Scholten, M. Cong, K. Iwaisako, Xiao Liu, Mingjun Zhang, C. Österreicher, F. Stickel, K. Ley, D. Brenner, T. Kisseleva (2012)Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice.
Gastroenterology, 143 3
JD Estes (2007)551
J Infect Dis, 195
RK Gershon (1970)723
B Langhans (2017)888
J Hepatol, 66
G. Lee (2018)The Balance of Th17 versus Treg Cells in Autoimmunity
International Journal of Molecular Sciences, 19
M. Oukka (2007)Interplay between pathogenic Th17 and regulatory T cells
Annals of the Rheumatic Diseases, 66
GC Huang (2004)1309
Biochem Biophys Res Commun, 324
HL Weiner, AP da Cunha, F Quintana, H Wu (2011)Oral tolerance
Immunol Rev, 241
Y. Ilan, R. Maron, A. Tukpah, T. Maioli, G. Murugaiyan, Kaiyong Yang, H. Wu, H. Weiner (2010)Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice
Proceedings of the National Academy of Sciences, 107
R. Bataller, S. Lemon (2012)Fueling fibrosis in chronic hepatitis C
Proceedings of the National Academy of Sciences, 109
YS Roh (2015)2009
Dig Dis Sci, 60
XF Sun (2014)2062
World J Gastroenterol, 20
Jinfang Zhu, H. Yamane, W. Paul (2010)Differentiation of effector CD4 T cell populations (*).
Annual review of immunology, 28
K. Yasuda, Yusuke Takeuchi, K. Hirota (2019)The pathogenicity of Th17 cells in autoimmune diseases
Seminars in Immunopathology, 41
A. Kimura, T. Kishimoto (2010)IL‐6: Regulator of Treg/Th17 balance
European Journal of Immunology, 40
ZM Liu (2015)553
Cell Mol Immunol, 12
M. Yuksel, Burak Demirbas, Özlem Mizikoğlu, Y. Tütüncü, T. Kanmaz, L. Oğuzkurt, Ç. Arıkan (2021)Examining the Hepatic Immune System in Children With Liver Disease With Fine Needle Aspiration
Journal of Pediatric Gastroenterology and Nutrition, 74
R Xu (2012)296
Cell Mol Immunol, 9
Guangcun Huang, Jin-sheng Zhang, Q. Tang (2004)Involvement of C/EBP-alpha gene in in vitro activation of rat hepatic stellate cells.
Biochemical and biophysical research communications, 324 4
B Langhans (2013)229
J Hepatol, 59
X Zhang (2017)1009
Med Sci Monit., 23
SC Katz (2011)1150
J Immunol., 187
www.nature.com/cddiscovery REVIEW ARTICLE OPEN Regulatory T cells (Tregs) in liver ﬁbrosis ✉ ✉ 1,7 2,7 2,7 1 1 3 4,5,6 1,6 Ke-jia Wu , Qu-fei Qian , Jin-ren Zhou , Dong-lin Sun , Yun-fei Duan , Xi Zhu , Kurt Sartorius and Yun-jie Lu © The Author(s) 2023 The ability of the human liver to both synthesize extracellular matrix(ECM), as well as regulate ﬁbrogenesis, are integral functions to maintaining homoeostasis. Chronic liver injury stimulates ﬁbrogenesis in response to the imbalance between ECM accumulation and ﬁbrosis resolution. Liver disease that induces ﬁbrogenesis is associated with multiple risk factors like hepatitis infection, schistosomiasis, alcohol, certain drugs, toxicants and emerging aetiology like diabetes and obesity. The activation of hepatic stellate cells (HSCs), whose function is to generate and accumulate ECM, is a pivotal event in liver ﬁbrosis. Simultaneously, HSCs selectively promote regulatory T-cells (Tregs) in an interleukin-2–dependent pattern that displays a dual relationship. On the one hand, Tregs can protect HSCs from NK cell attack, while on the other hand, they demonstrate an inhibitory effect on HSCs. This paper reviews the dual role of Tregs in liver ﬁbrogenesis which includes its promotion of immunosuppression, as well as its activation of ﬁbrosis. In particular, the balance between Tregs and the Th17 cell population, which produce interleukin (IL)-17 and IL-22, is explored to demonstrate their key role in maintaining homoeostasis and immunoregulation. The contradictory roles of Tregs in liver ﬁbrosis in different immune microenvironments and molecular pathways need to be better understood if they are to be deployed to manage this disease. Cell Death Discovery (2023) 9:53 ; https://doi.org/10.1038/s41420-023-01347-8 INTRODUCTION immune cells that respond to chronic inﬂammation, tissue Liver ﬁbrosis is generally considered to be the consequence of regeneration, ECM remodelling and ﬁbrogenesis . A hallmark ongoing chronic liver injury and a leading pathogenic factor of event of liver ﬁbrosis is the activation and expression of HSCs morbidity and mortality in chronic viral hepatitis and obesity- which are regulated by several immune mediators, including Th9, related fatty liver disease worldwide . Non-resolving liver Th22, Tregs, innate lymphoid cells (ILCs), mucosal-associated ﬁbrogenesis, stimulated by a wide range of risk factors, induces invariant T cells (MAIT), and γδT cells, along with their associated the activation of quiescent hepatic stellate cells (HSCs) into cytokines . In early-stage ﬁbrosis that is resolved, the immune myoﬁbroblasts that are the primary extracellular matrix (ECM)-cell response contributes to terminating HSC activation and ﬁbrous type that promotes ﬁbrous protein deposition and scarring . protein expression, however, in the case of ongoing liver disease, The severity and outcome of ﬁbrogenesis in liver disease can be the complicated interplay of these immune mediators often triggered by a wide range of risk factors including viral infection, promotes liver ﬁbrosis. A key change in the adaptive immune toxins, and a range of non-communicable diseases that contribute response is the mobilization of regulatory T(Tregs) cells that play to a build-up of fatty tissue in the liver. Chronic hepatitis infection, an immunosuppressive role to promote immune self-tolerance for instance, promotes liver ﬁbrosis that can translate into cirrhosis and homoeostasis. The Treg family includes natural Tregs(nTregs) and the onset of neoplasms (Chronic hepatitis→ liver ﬁbrosis→ that express the nuclear transcription factor FoxP3, as well as cell liver cirrhosis→ Liver Neoplasms) . In patients suffering from surface proteins CTLA-4 and CD25 and induced Tregs(iTregs) [8, 9]. chronic liver injury, progression to the end stage usually takes 20 An increase of Tregs in ﬁbroproliferative sites inﬂuences the to 40 years depending on whether both environmental and subsequent balance between tissue inhibitors of metalloproteina- genetic elements are causal factors . Early-stage ﬁbrosis is more se(TIMP) and matrix metalloproteinase(MMP) and Kupffer cell (KC) easily resolved while advanced liver ﬁbrosis can result in a range expression to promote ECM remodelling and ﬁbrogenesis . In of severe symptoms, such as cirrhosis, liver failure, and portal addition, the Treg/TH17 ratio plays a key role in the process of hypertension , When ﬁbrogenesis progresses to decompen- intrahepatic immune regulation and the dysregulation of this ratio sated cirrhosis, the survival period of patients is signiﬁcantly is a key characteristic of the progression of liver ﬁbrosis . shortened, and therapeutic options are eventually limited to liver Restoring Treg/Th17 balance can effectively immunize against transplantation . various intracorporal and extracorporeal pathogens, as well as Fibrogenesis as a result of liver injury involves a complex prevent excessive autoimmune self-harm . However, further interactome that includes the interaction of various types of research on Tregs and the Treg/Th17 role in the ﬁbrogenesis 1 2 Department of Hepatobiliary and Pancreatic Surgery, The Third Afﬁliated Hospital of Soochow University, Changzhou 213000, China. The First Afﬁliated Hospital of Nanjing 3 4 Medical University, Nanjing 210000, China. Department of infectious diseases, the First Peoples’ Hospital of Kunshan, 215300 Kunshan, China. Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg, South Africa. School of Laboratory Medicine and Molecular Sciences, University of Kwazulu-Natal, Durban, South 6 7 Africa. Africa Hepatopancreatobiliary Cancer Consortium, Mayo Clinic, Jacksonville, USA. These authors contributed equally: Ke-jia Wu, Qu-fei Qian, Jin-ren Zhou. email: email@example.com; firstname.lastname@example.org Received: 23 November 2022 Revised: 24 January 2023 Accepted: 27 January 2023 Ofﬁcial journal of CDDpress 1234567890();,: K. Wu et al. Fig. 1 The role of Treg in promoting ﬁbrosis. Liver ﬁbrosis is primarily induced by HSCs that promote TGF-β based production of myoﬁbroblasts that stimulate ECM-driven ﬁbrogenesis. Tregs can also activate HSCs to promote ﬁbrosis through the TGF-β pathway. Treg can + + + induce HSCs via the expression of IL-8. Treg cells with CD4 CD25 Foxp3 can be selectively expanded by HSCs in an IL-2–dependent pattern. Tregs can directly suppress NK cells from degranulating in the role of IL-8, TGF-β1, and CTLA-4 signalling pathways. Footnote: hepatic stellate cells (HSCs), transforming growth factor-β (TGF-β), extracellular matrix (ECM), matrix metalloproteinase (MMP), regulatory cells (Treg), kupffer call (KC), interleukin-2 (IL-2), natural killer cell (NK cell), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). interactome is needed to promote potential diagnostic and surface: CD25, CTLA-4, PD-L1, GITR, and HLA-DR [20, 21]. The therapeutic options. This review outlines the current under- expression and functions have signiﬁcant differences between standing of the role/s of Tregs on liver ﬁbrosis. First, we review the naïve and activated Tregs, suggesting another dimension that the known pathways of Tregs that promote ﬁbrogenesis and second tissue Tregs express higher levels of activation markers compared the role of Tregs and their related cytokines that suppress to blood. For example, activated effector Tregs (CD45RA- ﬁbrogenesis. Thirdly, we outline the potential effects of the Treg/ FOXP3high) express high levels of HLA-DR compared to naïve Th17 balance and their related cytokines on ﬁbrogenesis and Tregs (CD45RA FOXP3low) [22, 23] and activated Treg cells play a ﬁnally, we illustrate the complex Treg interactome and discuss the major role in ﬁbrogenesis. Although Treg cells only account for potential for Treg therapy to be exploited for the treatment of 5%-10% of the total CD4 T lymphocytes in peripheral blood , ﬁbrosis of the liver. their contribution to maintaining immune tolerance and homo- eostasis cannot be ignored. BACKGROUND AND ROLE OF TREGS Treg cells were ﬁrst discovered by GERSHON et al.  in the THE PRO-FIBROSIS FUNCTION OF TREG 1970s and were referred to as “suppressor cells” because of their Activated Tregs are essential during the healing period to end role in immune regulation. A later study in 1995 showed that inﬂammation and promote wound healing  and yet recent CD25 expression was a hallmark of these suppressor cells that evidence indicates that a large number of Tregs are distributed in were labelled for the ﬁrst time as Tregs . This study also the ﬁbrotic microenvironment in HCC patients. Interestingly, a + + demonstrated that the in vivo transfer of CD4 CD25 Treg- reduction in Tregs promoted the regression of ﬁbrosis  deﬁcient T cells triggered autoimmune disease in a mouse model. illustrating that Tregs play a prominent role in promoting ﬁbrosis + + + + + Conversely, autoimmune effects were retarded when CD4 CD25 [Fig. 1]. A report showed Treg cells with CD4 CD25 Foxp3 were cells were introduced. The prevailing view is that there are two selectively increased by HSCs in an interleukin-2–dependent main sub-types of Tregs determined by cellular origin, namely, pattern  explaining the abundance of Tregs in ﬁbrotic tissue natural Tregs(nTregs), which are differentiated in the thymus from [Fig. 1]. MMPs, the main enzyme involved in ECM degradation  progenitor cells derived from bone marrow, and inducible Tregs are produced primarily by KCs , however, even a low ratio of (iTregs), which are differentiated from peripheral naïve T cells to Tregs can repress KC expression of MMPs. Treg cells regulate the respond to infectious challenges. Except for nTregs and iTregs, balance of MMP/TIMP through KCs, thereby inhibiting the various studies have identiﬁed other T cells with regulatory resolution of ﬁbrosis  [Fig. 1]. properties, including T helper (Th)-like Treg subsets, CD8 Tregs, Experiments have shown that Tregs may inhibit KCs from Tr1 cells, and Th3 cells [14–17]. In addition, many researchers have secreting MMP in vivo through the TGF-β pathway  [Fig. 1]. A subdivided Treg cells into different subsets in different diseases parallel increase in collagen type I deposition and TGF-β1 Tre g according to the different expression of Treg cell surface cells was observed in lymphoid tissues of the simian immunode- molecules, such as “Treg B” that shows a higher expression of ﬁciency virus (SIV) -infected rhesus monkeys 7 days after inocula- hi lo + CD95, CCR4, and CD45RO within FOXP3 , CD127 Tregs in tion . These results indicate that TGF-β1 Treg cells have a aplastic anaemia . Transcription factor forkhead box protein 3 dichotomous response to immune activation; on the one hand, (FoxP3) is the most characteristic marker of Treg cells and plays an they can inhibit viral immune response while on the other hand, important role in Treg development and immune regulation. Tregs they can induce collagen deposition in lymphoid tissues, resulting mainly secrete IL-10, TGF-β, IL-35, and other cytokines, which in organ ﬁbrosis. enable the body to obtain immune tolerance by inhibiting the HSCs which are spread over the Disse space are generally differentiation and proliferation of NKT cells, macrophages, B cells, considered to be the hallmark cells of ﬁbrosis and the major and so on . Treg cells express the following molecules on their source of myoﬁbroblasts and activation of HSCs is the initiating Cell Death Discovery (2023) 9:53 K. Wu et al. Fig. 2 The role of Treg in inhibiting ﬁbrosis. IL-2 as well as its complexes accelerate Tregs expressing CD39 in the liver, thereby inhibiting the multiplication of CD8 T cells and its function of generating TNF-α and osteopontin, which can reduce biliary ﬁbrosis. Tregs can regulate the high high pro-ﬁbrotic roles of Th2 cells and Ly-6C CCR2 inﬂammatory monocytes/macrophages that secrete IL-4 and TGF-β respectively, interestingly, IL-10 secreted by Tregs may regulate them. Tregs can regulate the TGF-β-IDO signalling pathway to enhance the function of hAMSC that repress liver ﬁbrosis. Tregs promoting the expression of amphiregulin can inhibit the development of ﬁbrosis by promoting the proliferation of hepatocytes. In CCL4-induced liver ﬁbrosis, rapamycin has an effective protective effect on the liver. Rapamycin signiﬁcantly + + increased the functional activity of CD4 CD25 Tregs and enhanced the inhibitory ability of Tregs on HSCs activation. Tregs can repress MCP- 1 which plays an important role in liver ﬁbrosis by activating HSC production. Tregs can directly repress CD4 T cell expression that reduces IFN-γ activated HSCs. Tregs also directly promote amphiregulin to repress liver ﬁbrosis. Footnote: interleukin (IL), regulatory cells (Treg), transforming growth factor-α (TGF-α), T helper cell (Th), indoleamine 2,3-dioxygenase (IDO), human amniotic mesenchymal stromal cell (hAMSC), carbon tetrachloride(CCL4), hepatic stellate cells (HSCs), monocyte chemotactic protein-1 (MCP-1), Interferon-γ (IFN-γ). event of hepatic ﬁbrosis. HSCs themselves can regulate the and α-SMA regions), it has also been demonstrated that deletion development of ﬁbrosis. On the one hand, in the presence of of IL-8 can inhibit the activation of HSCs, however, the immune inﬂammatory stimuli, resting HSCs are often activated and regulatory function of Treg cells was not affected, illustrating that converted into myoﬁbroblast-like cells and generate large IL-8 Tregs can promote ﬁbrosis  [Fig. 1]. amounts of ECM and cytokines [Fig. 1]. On the other hand, In summary, the complex Treg interactome reveals that Treg activated HSCs can secrete MMPs to degrade ECM  [Fig. 1]. It expression can secrete IL-8 to activate HSCs that, in turn, can can be said that HSCs largely determine the promotion or secrete IL-2 to induce Treg expression. Tregs can secrete TGF- β to regression of liver ﬁbrosis. In addition, TGF-β1 secreted by repress KC expression of MMPs that degrade ECM accumulation to macrophages is the strongest known activator of HSCs . promote ﬁbrogenesis and Treg-secreted TGF- β promotes HSC- Meanwhile, the two most important cytokines secreted by Tregs derived myoﬁbroblasts. Tregs also promote ﬁbrogenesis by are TGF-β and IL-10  and Tregs can activate HSCs to promote secreting Il-8, TGF- β and CTLA-4 to repress NK repression of ﬁbrosis through the TGF-β pathway [Fig. 1]. HSC activation. Tregs thus interact with multiple cell types and Of note, HBV which is one of the main pathogenic factors activate a range of cell–cell interactions with HSCs, NKs and KCs to leading to liver ﬁbrosis can induce the generation of immuno- promote ﬁbrogenesis (Fig. 1). suppressive cells, such as Tregs, MDSCs, and NK-REG cells, through the immunosuppressive cascade, undue induction can lead to adverse outcomes, such as liver ﬁbrosis and even HCC . HBV- THE ANTI-FIBROSIS FUNCTION OF TREG induced Tregs may suppress the antiﬁbrotic function of NK cells It is interesting to note that TGF-β generated by Tregs in HCV is and directly suppress NK cells from degranulating in the role of IL- inversely associated with the regression of liver inﬂammation and 8, TGF-β1, and CTLA-4 signalling pathways [Fig. 1]. Tregs can also ﬁbrosis, even though cytokine TGF-β is a well-established pro- have an indirect protective effect on HSCs from NK cell’s attack on ﬁbrotic element, suggesting that TGF-β also has antiﬁbrotic account of suppressing the expression of MICA/B on HSCs through properties . According to the observation, the large number TGF-β1 and IL-8 . Tregs can inhibit NK cells and M1 KCs from of highly differentiated and activated Tregs distributed to participating in the immune regulation of liver ﬁbrosis, and its inﬁltrating chronic HCV-infected livers can lead to a limitation of immunosuppressive regulation contributes to the development of the degree of ﬁbrosis.  Tregs in the peripheral blood of HCV chronic inﬂammation, thus maintaining liver ﬁbrosis . There- patients can suppress the proliferation of HCV-speciﬁc T cells and fore, by cutting off the pathway of Treg action on NK cells and IFN-γ . In addition, the depletion of Tregs restored the restoring antiviral T-cell responses, the development of inﬂamma- secretion of IFN-γ by CD4 T cells  [Fig. 2]. This indicates that tion and injury can be limited, and HSCs, as a crucial element of Tregs in an HCV-induced environment are pivotal in the limitation liver ﬁbrosis, can be reduced, thereby limiting the development of of collateral injury and homoeostasis maintenance by inhibiting liver ﬁbrosis. an intemperate immune response. In addition, according to experimental observation, Treg cells Treg cells can guard against HIV-1-induced liver ﬁbrosis, and the have been shown to proliferate during chronic HCV infection  mechanism may be related to the activation of HSCs, liver injury, and are enriched in liver ﬁbrosis tissue to protect HSCs from NK and hepatitis . In this regard, one study investigating HIV-1- cell attack . Interestingly, an abundance of T cells with induced liver ﬁbrosis deleted Treg cells with denileukin diftitox. By + + + IL-8 CD4 Foxp3 are found in HCV liver tissue (mainly in ﬁbrotic measuring various plasma indicators, Only HIV-1+ denileukin Cell Death Discovery (2023) 9:53 K. Wu et al. diftitox mice in infection showed a signiﬁcant increase in ALT value for the treatment of liver cirrhosis  [Fig. 2]. It was also levels after 20 days. Similarly, serum hyaluronic acid levels, also a proved that mesenchymal stem cells(MSCs) as well as MSC- sign of liver injury and ﬁbrosis, were only elevated in infected HIV- conditioned medium (MSC-CM) both inhibited necroinﬂammatory 1+ denileukin diftitox mice after 20 days. Therefore, HIV-1 and ﬁbrogenesis in a chronic liver injury model, however, the infection together with Tregs depletion causes liver inﬂammation second therapy had a better effect. In this regard, the activation of and ultimate ﬁbrosis. Using Denileukin Diftitox alone highly up- Treg and Th2 cells, and decreased the number of Th17 cells . regulated the expression of human inﬂammatory chemokines Another study showed that umbilical cord-derived MSCs selected McP-1 and MIP-1α in the liver [Fig. 2]. It revealed that McP-1, which by individual heterogeneity have the function of promoting Tregs is closely related to Tregs, may play an important role in the and have been proven to improve the recovery of liver ﬁbrosis in process of ﬁbrosis initiated by inﬂammation . mice . Tregs can also alleviate the pathological process of While protecting the body from physiological factors, inﬂam- hepatic steatosis and high-calibre abnormal blood cholesterol and matory cell immunity also promotes liver injury and ﬁbrosis. Tregs glucose metabolism, and aberrant levels of liver enzymes in leptin- can inhibit inﬂammatory cell immunity, thereby inhibiting ﬁbrosis. deﬁcient OB/OB mice , indicating the potential curative effect It has been found that chronic liver inﬂammation induced by of diabetes and prevention of early hepatic ﬁbrosis by carbon tetrachloride (CCL4) injection tends to preferentially inducing Tregs. expand liver Treg cells, thereby protecting liver function and In summary, the complex Treg interactome that induces an anti- avoiding ﬁbrosis . In CCL4-induced liver ﬁbrosis, rapamycin has ﬁbrotic effect involves the interaction between Tregs and a range an effective protective effect on the liver. Further studies found of liver cell types and signalling pathways. Rapamycin can that rapamycin signiﬁcantly increased the functional activity of effectively protect the liver by enhancing the inhibitory ability of + + CD4 CD25 Treg, and enhanced the inhibitory ability of Tregs on Treg to the activation of HSCs. Tregs repress HSC activation by HSCs activation  [Fig. 2]. α-SMA is a hallmark of the activation repressing MCP-1-induced HSC activation and by repressing CD4 of HSCs and a sensitive indicator of myoﬁbroblasts . It was also T-cell secretion of IFN-γ. This anti-ﬁbrotic interactome also found that increased Treg cell levels, induced by rapamycin, includes repression of Th2/IL-4 driven ﬁbrosis, the repression of effectively decreased α-SMA expression . Alternatively, Treg macrophage/TGF-β initiated ﬁbrosis, and the promotion of hAMSC depletion enhances the immunologic function of inﬂammatory repression of ﬁbrosis by promotion of TGF-β/IDO induced hAMSC. cells and drives pro-ﬁbrotic T-helper 2 cells(Th2) that induce IL-4 Tregs repress ﬁbrosis by inducing amphiregulin repression of activation. Th1 cells, which secrete IFN-γ and Th2 cells which ﬁbrosis and Tregs can induce IL-2/CD39 repression of CD8 T-cells generate IL-4, are antiﬁbrotic and pro-ﬁbrotic T-helper cell subsets, to suppress ﬁbrosis because they reduce CD8 T-cell expression of respectively. Treg depletion will break the balance between these TGF-α and osteopontin. It is, therefore, apparent that Tregs two subsets, thus leading to ﬁbrosis . Th2 cells and Ly- interact with multiple cell types in multiple pathways to repress high high 6C CCR2 inﬂammatory monocytes/macrophages both have liver ﬁbrosis (Fig. 2). a pro-ﬁbrotic function by secreting IL-4 and TGF-β respectively, although IL-10 secreted by Tregs may regulate them  [Fig. 2]. This illustrates that although Tregs can promote ﬁbrosis, most THE TREG/TH17 BALANCE IN LIVER FIBROSIS evidence suggests that Treg cells have an anti-ﬁbrotic effect, Th17 cells are a subpopulation of CD4 T cells that speciﬁcally primarily due to their immunosuppressive effect on IL-10 secretion express RORγt and secrete signature cytokines IL-17, IL-22, and IL- . In addition, Tregs also secrete amphiregulin, an important 23 . Recent studies have found that Th17 and the cytokines it factor involved in tissue repair and regeneration in a variety of secretes have a signiﬁcant impact on the pathological process of models of inﬂammation . In one study, amphiregulin inhibited liver ﬁbrosis [64–66].Th17 cells are bound up with Treg cells. First, the development of ﬁbrosis by promoting the proliferation of both Th17 and Treg cells are derived from naive CD4 T cells, and hepatocytes  [Fig. 2]. second, they both require TGF-β signalling to differentiate. In a model of acute disease induced by bile duct ligation(BDL), Interestingly, the two cells that are so similar have diametrically Tregs in the liver reduced T lymphocyte function and effectively contrary functions: Th17 cells contribute to the development of limited liver ﬁbrosis  demonstrating the critical role of Tregs in inﬂammation and autoimmunity, while Treg cells suppress the maintaining immune suppression. Furthermore, in the BDL model, above-mentioned phenomena and promote immune homoeos- the exhaustion of Tregs increased the generation of inﬂammatory tasis  [Fig. 3]. In vitro HSCs can be activated by Th17 to develop mediators, such as chemokines and cytokines, and promoted the ﬁbrosis while Tregs can inhibit the activation of HSCs . inﬁltration of Th17 and CD8 T cells in the ﬁbrotic liver , Some viruses can persistently damage liver tissue, eventually suggesting that Tregs can suppress the pro-ﬁbrotic effects of Th17 leading to cirrhosis, and Treg/Th17 balance can prevent excessive and CD8 T cells. In a mouse model with sclerosing cholangitis, liver damage during viral infection. Some studies have found that treatment with low-dose IL-2 induced the expansion of intrahe- in acute hepatitis A virus(HAV) patients, serum IL-17 level has a patic Tregs, thereby reducing biliary injury and ﬁbrosis. The positive correlation with the degree of liver damage, and the mechanism may be Il-2 precipitated, as well as its complexes, that frequency of hepatic resident and circulating Tregs is negatively promote Tregs expressing CD39 in the liver, thereby inhibiting the correlated with liver injury . Similarly, other researchers have multiplication of CD8 T cells and its function of generating TNF-α demonstrated that the quantity and proportion of Th17 cells in and osteopontin, which can reduce biliary ﬁbrosis  [Fig. 2]. the liver and peripheral blood are increased in acute and chronic Human amniotic mesenchymal stromal cells (hAMSC) can liver injury [69, 70] demonstrating the strong pro-ﬁbrotic function regulate the immune response in a variety of diseases and of Th17. demonstrate a powerful regenerative repair ability similar to stem It has been found that a selective Rho/RhoA-associated kinase cells . The combination of Treg and hAMSC infusion rescued (ROCK) inhibitor (Fasudil) can effectively inhibit cell differentiation low-grade liver ﬁbrosis compared with injecting Treg or hAMSC of Th17 and its ability to express IL-17 [Fig. 3]. Using this inhibitor respectively. The reason may be that Tregs can improve the and the upregulation of Tregs can limit liver ﬁbrosis in mice expression of hepatocyte growth factor (HGF) and the ability of caused by Schistosoma japonicum infection . Treg/Th17 play hAMSC to differentiate  [Fig. 2]. The two principal cytokines opposite roles in the development of HBV-LF ﬁbrosis by affecting expressed by Tregs are TGF-β and IL-10 [34, 59]. Experiments have liver injury and hematopoietic stem cell function . This is shown that Tregs can regulate the TGF-β-IDO signalling pathway demonstrated, not only in liver ﬁbrosis, but also proved that Treg/ and then enhance the function of hAMSC, and combination Th17 balance exists in several inﬂammatory and autoimmune therapy of Tregs and hAMSC infusion has great potential research diseases, including systemic lupus erythematosus (SLE), Cell Death Discovery (2023) 9:53 K. Wu et al. Fig. 3 The relationship between Tregs and Th17. Treg and Th17 cells are convertible in different immune microenvironments. Treg cells can be transformed into cells expressing IL-17 in the presence of IL-6 and IL-21, as well as IL-2 and IL-1β. Fasudil can effectively inhibit cell differentiation of Th17 and its ability to express IL-17. Using this inhibitor and upregulation of Treg can limit liver ﬁbrosis in mice caused by Schistosoma japonicum infection. Rapamycin signiﬁcantly reduced the level of Th17 cells in the CCL4-induced liver ﬁbrosis model, it even can enhance the inhibitory function of Treg on HSCs.IL-35 has a similar function compared with the formers. Il-6 has an extraordinary effect on Th17/Treg balance. Il-6 can induce the development of naïve T cells into Th17 cells in the existence of TGF-β. However, its effect on Tregs has two sides. But overall, IL-6 still tilts the balance between Tregs and Th17 toward Th17 cells. DCs play dual roles in the pathways of Treg. Footnote: regulatory cells (Treg), T helper cell (Th), interleukin (IL), retinoid-related orphan receptor gamma t (RORγt), carbon tetrachloride (CCL4), hepatic stellate cells (HSCs), dendritic cells (DC). rheumatoid arthritis, and primary biliary cirrhosis, [73–75]. There- amplify the functions of virus-speciﬁc Treg cells while also fore, we deduce that the Treg/Th17 balance may be an important inhibiting Th17 cell differentiation  [Fig. 3]. It is this effect of biomarker of immune homoeostasis, reﬂecting some extent the IL-35 that could lead to the break of balance, which causes balance between the pro-inﬂammatory and anti-inﬂammatory persistent HBV infection and chronic disease, ultimately leading to abilities of the body. irreversible liver ﬁbrosis. It was also found that rapamycin The balance of Treg /Th17 is so important in the progression of signiﬁcantly reduced the level of Th17 cells and the expression cirrhosis that some scholars have considered it an independent level of ROR-γT in the CCL4-induced liver ﬁbrosis model. At the predictor of decompensated cirrhosis . It has also been same time, rapamycin can lead to a signiﬁcant increase in Treg suggested that the Treg/Th17 ratio may be used as a measure of frequency and Foxp3 expression and it can even enhance the disease severity in animal models and human diseases . Zhai inhibitory function of Tregs on HSCs  [Fig. 3]. From the et al. showed that the ratio of Th17 to Treg had a negative different effects of rapamycin on Treg and Th17 expression, as correlation with the survival rate of patients with acute-on-chronic well as its inhibition of the development of ﬁbrosis, rapamycin liver failure(ACLF) . The experimental results of Yu et al. also appears to play an important role in the regulation of Th17/Treg showed a similar conclusion, and they found that the ratio of Treg balance. to Th17 in the survival group was higher than the ratio in the non- As mentioned above, Tregs play different roles under different survival group of HBV-LC patients . Nan et al. observed that cytokine conditions. However, increasing data indicate that Treg compared with the control group, the cell quantities of Treg and and Th17 cells are convertible in different immune microenviron- Th17 cells in the chronic HBV patients’ peripheral blood were ments. For instance, Treg cells can be transformed into cells larger, and the proliferation of Th17 cells was more obvious than expressing IL-17 in the presence of IL-6 and IL-21 [Fig. 3], while that of Treg cells in the acute attack, and this series of changes led Th17 cells can be transformed into Th1/2 cells in the existence of to the decrease of Treg/Th17 ratio . Rong et al. reported that IL-4 or IL-12 . Deknuydt et al found that nTregs can be the number of Th17 cells and the level of ROR-γT expression in the transformed into Th17 cells under the induction of IL-2 in the peripheral blood of patients suffering from primary biliary cirrhosis immune microenvironment where the activated APC and mono- were signiﬁcantly increased. However, the quantity of Treg cells cytes after microbial stimulation are considered to be the most and the expression of FoxP3 were signiﬁcantly decreased . effective factors in promoting Treg transformation [Fig. 3]. Further Another study demonstrated that a lower ratio of Treg to Th17 studies showed that IL-1β could mediate the conversion of Tregs often indicates greater progression of liver ﬁbrosis in HBV-infected to Th17 [Fig. 3], which may be related to the downregulation of patients . These results suggest that the imbalance between Foxp3 . Over the last few decades, the main research Th17 and Treg is strongly associated with the development of liver directions on liver ﬁbrosis are Th1 and Th2-focused. Recent cirrhosis, and the balance of them may be a key prognostic advances in immunology have focused on two new T cell subsets indicator for HBV-LC, and an increased Treg/Th17 ratio may (Treg and Th17 cells) that supplement and reﬁne the classical indicate a better prognosis, whereas a poor prognosis otherwise. theory of Th1/Th2  interplay. For example, Il-6 has a signiﬁcant In addition, lL-35 has a crucial impact on balancing Treg and effect on Th17/Treg balance  and can induce the development Th17 in acute and chronic HBV infection. It has been found to of naïve T cells into Th17 cells in the presence of TGF-β. On the Cell Death Discovery (2023) 9:53 K. Wu et al. contrary, IL-6 has both direct and indirect effects on Treg cells. On investigate different signalling pathways that may affect Th17/ the one hand, IL-6 suppressed the induction of Treg cell Tregs’ contribution to liver-speciﬁc therapies. Finally, we have conversion by TGF-β without affecting the number and function attempted to highlight the complex Treg interactome in its of nTregs [85, 86] [Fig. 3].On the other hand, there are several lines promotion of ﬁbrosis, in its alternate anti-ﬁbrotic role and lastly of evidence that IL-6 has immunomodulatory effects supporting how the Treg/Th17 ratio inﬂuences pro and anti-ﬁbrotic activity. Tregs number and function, which are mainly because LPS- The multiplicity of interacting cells with Tregs in the liver, as well stimulated dendritic cells produce IL-6 which activates as the signalling pathways suggest that multiple therapeutic STAT3 signalling to eventually keep DCs in an immature state options can be further explored, however, a fuller understanding with low CD80 and MHC-II levels, as well as increase IL-10 of liver ﬁbrogenesis will be needed. production to promote Treg cells  [Fig. 3]. But overall, IL-6 still tilts the balance between Tregs and Th17 toward Th17 cells. In summary, Th17 and Treg cells are integrally involved in the DATA AVAILABILITY immune response in the progression of liver ﬁbrosis. Their balance All data included in this study are available upon request by contact with the determines the maintenance of body homoeostasis and is very corresponding author. important for the prevention or prognosis of liver ﬁbrosis. The complex Treg interactome that results in the differentiation of naïve T-cells inﬂuencing the Treg/Th17ratio and its inﬂuence on ﬁbrogen- REFERENCES esis involves the interaction of a differential Treg exposure to a 1. Hernandez-Gea V, Friedman SL. Pathogenesis of liver ﬁbrosis. Annu Rev Pathol. range of cytokines, as well as cell-to-cell signalling pathways. Tregs 2011;6:425–56. exposure to IL-6/-2/-21/-IL-1β can be transformed into Th17 to 2. Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver ﬁbrosis and its promote HSC initiate ﬁrogenesis. Naïve T-cells differentiation to Th17 regression. Nat Rev Gastroenterol Hepatol. 2021;18:151–66. 3. Friedman SL. Liver ﬁbrosis—from bench to bedside. J Hepatol. 2003;38:S38–53. promotes IL-17-promoted HSC activation. On the other hand, 4. Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting future complications of rapamycin/fasudil/Il-35 expression can promote Treg to inhibit chronic hepatitis C in the United States. Liver Transpl. 2003;9:331–8. HSC activity and inhibit Th17 to promote HSC activation. DCs can 5. Bataller R, Brenner DA. Liver ﬁbrosis. J Clin Investig. 2005;115:209–18. secrete IL-6/ TGF-β that repress naïve T-cell differentiation to Tregs 6. Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev while TGF-β promotes Th17 differentiation (see Fig. 3). Gastroenterol Hepatol. 2017;14:397–411. 7. Wan M, Han J, Ding L, Hu F, Gao P. Novel immune subsets and related cytokines: emerging players in the progression of liver ﬁbrosis. Front Med. 2021;8:604894. CONCLUSION 8. Ohkura N, Sakaguchi S. Transcriptional and epigenetic basis of Treg cell devel- The mechanism of Tregs in liver ﬁbrosis has not been completely opment and function: its genetic anomalies or variations in autoimmune dis- eases. Cell Res. 2020;30:465–74. elucidated, Whether Tregs express pathogenicity or host protec- 9. Liu ZM, Wang KP, Ma J, Guo, Zheng S. The role of all-trans retinoic acid in the tive functions often depends on environmental stimuli. Because of biology of Foxp3+ regulatory T cells. Cell Mol Immunol. 2015;12:553–7. the duality of Tregs in different environments, this area of research 10. Zhang X, Feng M, Liu X, Bai L, Kong M, Chen Y, et al. Persistence of cirrhosis is has become a ‘hotspot’ in recent years. This is important because maintained by intrahepatic regulatory T cells that inhibit ﬁbrosis resolution by the role of Tregs is involved in several risk factors contributing to regulating the balance of tissue inhibitors of metalloproteinases and matrix liver ﬁbrosis, such as hepatitis virus, schistosomiasis, alcohol, metalloproteinases. Transl Res. 2016;169:67–79e1–2. certain drugs, toxicants and NCDs. In summary, liver ﬁbrosis is 11. Sun XF, Gu L, Deng WS, Xu Q. Impaired balance of T helper 17/T regulatory cells mainly divided into two aspects, one is the damage of in carbon tetrachloride-induced liver ﬁbrosis in mice. World J Gastroenterol. hepatocytes or cholangiocytes, and the other is the disorder of 2014;20:2062–70. 12. Gershon RK, Kondo K. Cell interactions in the induction of tolerance: the role of ECM production. In response to environmental cues for ﬁbre thymic lymphocytes. Immunology 1970;18:723–37. resolution or ﬁbre formation, Tregs show different transcriptional 13. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance changes. We can conclude that the transcriptional capacity of maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Tregs is tissue-speciﬁc and can be expressed differently in Breakdown of a single mechanism of self-tolerance causes various autoimmune response to different environmental or inﬂuencing factors. More- diseases. J Immunol. 1995;155:1151–64. over, the role of Tregs can even express reverse effects at different 14. Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. stages of the disease. This is aptly demonstrated by research that Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. shows that Treg cells were depleted early in bleomycin-induced Immunol Rev. 2006;212:28–50. ﬁbrosis by anti-CD25 antibody and the prognosis of ﬁbrosis was 15. Weiner HL, da Cunha AP, Quintana F, Wu H. Oral tolerance. Immunol Rev. 2011;241:241–59. improved, however, when Treg cells were depleted late in the 16. O’Garra A, Vieira P. Regulatory T cells and mechanisms of immune system control. disease, ﬁbrosis was exacerbated . Besides, the role of Tregs in Nat Med. 2004;10:801–5. the same disease often has two sides, the function of Tregs in the 17. Halim L, Romano M, McGregor R, Correa I, Pavlidis P, Grageda N, et al. An Atlas of pathological process of hepatitis B is contradictory and complex. human regulatory T helper-like cells reveals features of Th2-like Tregs that sup- On the one hand, Tregs can inhibit the promoters of liver ﬁbrosis port a tumorigenic environment. Cell Rep. 2017;20:757–70. (HSCs), yet at the same time, this can provide a haven for the 18. Kordasti S, Costantini B, Seidl T, Perez Abellan P, Martinez Llordella M, McLornan hepatitis B virus to avoid immune detection . D, et al. Deep phenotyping of Tregs identiﬁes an immune signature for idiopathic Studies over the past decade have shown that Th17 cells have a aplastic anemia and predicts response to treatment. Blood 2016;128:1193–205. proinﬂammatory response in almost all tissues . The effect of 19. Iman M, Rezaei R, Azimzadeh Jamalkandi S, Shariati P, Kheradmand F, Salimian J. Th17/Treg immunoregulation and implications in treatment of sulfur mustard Tregs is not always opposite to Th17, instead, under certain gas-induced lung diseases. Expert Rev Clin Immunol. 2017;13:1173–88. conditions, the two can act synergistically. The Treg/Th17 20. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, et al. relationship may also be related to different irritants, triggers of Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells liver injury, stages of ﬁbrosis, and interactions between different constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp immune mediators. Due to the dichotomous nature of Tregs, Med. 2000;192:303–10. perhaps targeting liver ﬁbrosis by immune cells can open a new 21. Botta D, Fuller MJ, Marquez-Lago TT, Bachus H, Bradley JE, Weinmann AS, et al. path for patients. Furthermore, Treg/Th17 interaction may help us Dynamic regulation of T follicular regulatory cell responses by interleukin 2 analyze the disease status, judge the prognosis of patients and during inﬂuenza infection. Nat Immunol. 2017;18:1249–60. promote diagnostic and therapeutic options to manage liver 22. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional deli- neation and differentiation dynamics of human CD4+ T cells expressing the ﬁbrosis. Future research is needed to understand the mechanism FoxP3 transcription factor. Immunity 2009;30:899–911. and balance of Treg and Th17 cells in liver tissue, as well as Cell Death Discovery (2023) 9:53 K. Wu et al. 23. Yuksel M, Demirbas B, Mizikoglu O, Tutuncu Y, Kanmaz T, Oguzkurt L, et al. 49. Xu R, Zhang Z, Wang FS. Liver ﬁbrosis: mechanisms of immune-mediated liver Examining the Hepatic immune system in children with liver disease with ﬁne injury. Cell Mol Immunol. 2012;9:296–301. needle aspiration. J Pediatr Gastroenterol Nutr. 2022;74:200–7. 50. Louis H, Van Laethem JL, Wu W, Quertinmont E, Degraef C, Van den Berg K. et al. 24. Albany CJ, Trevelin SC, Giganti G, Lombardi G, Scottà C. Getting to the heart of Interleukin-10 controls neutrophilic inﬁltration, hepatocyte proliferation, and liver the matter: The Role of Regulatory T-Cells (Tregs) in Cardiovascular Disease (CVD) ﬁbrosis induced by carbon tetrachloride in mice. Hepatology 1998;28:1607–15. and atherosclerosis. Front Immunol. 2019;10:2795. 51. Zhang C, Li L, Feng K, Fan D, Xue W, Lu J. ‘Repair’ treg cells in tissue injury. Cell 25. Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self- Physiol Biochem. 2017;43:2155–69. tolerance and negative control of immune responses. Annu Rev Immunol. 52. Ito M, Komai K, Mise-Omata S, Iizuka-Koga M, Noguchi Y, Kondo T, et al. Brain 2004;22:531–62. regulatory T cells suppress astrogliosis and potentiate neurological recovery. 26. Ormandy LA, Hillemann T, Wedemeyer H, Manns MP, Greten TF, Korangy F. Nature 2019;565:246–50. Increased populations of regulatory T cells in peripheral blood of patients with 53. Berasain C, Avila MA. Amphiregulin. Semin Cell Dev Biol. 2014;28:31–41. hepatocellular carcinoma. Cancer Res. 2005;65:2457–64. 54. Katz SC, Ryan K, Ahmed N, Plitas G, Chaudhry UI, Kingham TP, et al. Obstructive 27. Jiang G, Yang HR, Wang L, Wildey GM, Fung J, Qian S, et al. Hepatic stellate cells jaundice expands intrahepatic regulatory T cells, which impair liver T lymphocyte preferentially expand allogeneic CD4+ CD25+ FoxP3+ regulatory T cells in an IL- function but modulate liver cholestasis and ﬁbrosis. J Immunol. 2011;187:1150–6. 2-dependent manner. Transplantation 2008;86:1492–502. 55. Roh YS, Park S, Lim CW, Kim B. Depletion of Foxp3+ regulatory T cells promotes 28. Duarte S, Baber J, Fujii T, Coito AJ. Matrix metalloproteinases in liver injury, repair proﬁbrogenic Milieu of cholestasis-induced liver injury. Dig Dis Sci. and ﬁbrosis. Matrix biology: journal of the International Society for. Matrix Biol. 2015;60:2009–18. 2015;44-46:147–56. 56. Taylor AE, Carey AN, Kudira R, Lages CS, Shi T, Lam S, et al. Interleukin 2 promotes 29. Hemmann S, Graf J, Roderfeld M, Roeb E. Expression of MMPs and TIMPs in liver hepatic regulatory T cell responses and protects from biliary ﬁbrosis in murine ﬁbrosis—a systematic review with special emphasis on anti-ﬁbrotic strategies. J sclerosing cholangitis.Hepatology. 2018;68:1905–21. Hepatol. 2007;46:955–75. 57. Silini AR, Magatti M, Cargnoni A, Parolini O. Is immune modulation the 30. Feng M, Wang Q, Zhang F, Lu L. Ex vivo induced regulatory T cells regulate mechanism underlying the beneﬁcial effects of amniotic cells and their deriva- inﬂammatory response of Kupffer cells by TGF-beta and attenuate liver ischemia tives in regenerative medicine? Cell Transpl. 2017;26:531–9. reperfusion injury. Int Immunopharmacol. 2012;12:189–96. 58. Deng Z, Zhou J, Mu X, Gu J, Li X, Shao Q, et al. Regulatory T cells improved the 31. Estes JD, Wietgrefe S, Schacker T, Southern P, Beilman G, Reilly C, et al. Simian anti-cirrhosis activity of human amniotic mesenchymal stem cell in the liver by immunodeﬁciency virus-induced lymphatic tissue ﬁbrosis is mediated by trans- regulating the TGF-beta-indoleamine 2,3-dioxygenase signaling. Front Cell Dev forming growth factor beta 1-positive regulatory T cells and begins in early Biol. 2021;9:737825. infection. J Infect Dis. 2007;195:551–61. 59. Nono JK, Lutz MB, Brehm K. Expansion of host regulatory T cells by secreted 32. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells products of the tapeworm Echinococcus multilocularis. Front Immunol. of the liver. Physiol Rev. 2008;88:125–72. 2020;11:798. 33. Koyama Y, Brenner DA. Liver inﬂammation and ﬁbrosis. J Clin Investig. 60. Huang B, Cheng X, Wang H, Huang W, la Ga Hu Z, Wang D, et al. Mesenchymal 2017;127:55–64. stem cells and their secreted molecules predominantly ameliorate fulminant 34. Bertolini TB, Biswas M, Terhorst C, Daniell H, Herzog RW, Piñeros AR. Role of orally hepatic failure and chronic liver ﬁbrosis in mice respectively. J Transl Med. induced regulatory T cells in immunotherapy and tolerance. Cell Immunol. 2016;14:45. 2021;359:104251. 61. Xie Y, Liu S, Wang L, Yang H, Tai C, Ling L, et al. Individual heterogeneity screened 35. Kondo Y, Shimosegawa T. Signiﬁcant roles of regulatory T cells and myeloid umbilical cord-derived mesenchymal stromal cells with high Treg promotion derived suppressor cells in hepatitis B virus persistent infection and hepatitis B demonstrate improved recovery of mouse liver ﬁbrosis. Stem Cell Res Ther. virus-related HCCs. Int J Mol Sci. 2015;16:3307–22. 2021;12:359. 36. Langhans B, Alwan AW, Krämer B, Glässner A, Lutz P, Strassburg CP, et al. Reg- 62. Ilan Y, Maron R, Tukpah AM, Maioli TU, Murugaiyan G, Yang K, et al. Induction of ulatory CD4+ T cells modulate the interaction between NK cells and hepatic regulatory T cells decreases adipose inﬂammation and alleviates insulin resis- stellate cells by acting on either cell type. J Hepatol. 2015;62:398–404. tance in ob/ob mice. Proc Natl Acad Sci USA. 2010;107:9765–70. 37. Zhang X, Lou J, Bai L, Chen Y, Zheng S, Duan Z. Immune regulation of intrahe- 63. Yasuda K, Takeuchi Y, Hirota K. The pathogenicity of Th17 cells in autoimmune patic regulatory T cells in ﬁbrotic livers of mice. Med Sci Monit. 2017;23:1009–16. diseases. Semin Immunopathol. 2019;41:283–97. 38. Langhans B, Nischalke HD, Krämer B, Hausen A, Dold L, van Heteren P, et al. 64. Lan RY, Salunga TL, Tsuneyama K, Lian ZX, Yang GX, Hsu W, et al. Hepatic IL-17 Increased peripheral CD4(+) regulatory T cells persist after successful direct- responses in human and murine primary biliary cirrhosis. J Autoimmun. acting antiviral treatment of chronic hepatitis C. J Hepatol. 2017;66:888–96. 2009;32:43–51. 39. Langhans B, Krämer B, Louis M, Nischalke HD, Hüneburg R, Staratschek-Jox A, 65. Wang L, Chen S, Xu K. IL-17 expression is correlated with hepatitis B‑related liver + + et al. Intrahepatic IL-8 producing Foxp3 CD4 regulatory T cells and ﬁbrogenesis diseases and ﬁbrosis. Int J Mol Med. 2011;27:385–92. in chronic hepatitis C. J Hepatol. 2013;59:229–35. 66. Sun HQ, Zhang JY, Zhang H, Zou ZS, Wang FS, Jia JH. Increased Th17 cells 40. Li J, Qiu SJ, She WM, Wang FP, Gao H, Li L, et al. Signiﬁcance of the balance contribute to disease progression in patients with HBV-associated liver cirrhosis. J between regulatory T (Treg) and T helper 17 (Th17) cells during hepatitis B virus viral Hepat. 2012;19:396–403. related liver ﬁbrosis. PloS One. 2012;7:e39307. 67. Lee GR. The balance of Th17 versus treg cells in autoimmunity. Int J Mol Sci. 41. Claassen MA, de Knegt RJ, Tilanus HW, Janssen HL, Boonstra A. Abundant 2018;19:730. numbers of regulatory T cells localize to the liver of chronic hepatitis C infected 68. Choi YS, Lee J, Lee HW, Chang DY, Sung PS, Jung MK, et al. Liver injury in acute patients and limit the extent of ﬁbrosis. J Hepatol. 2010;52:315–21. hepatitis A is associated with decreased frequency of regulatory T cells caused by 42. Cabrera R, Tu Z, Xu Y, Firpi RJ, Rosen HR, Liu C. et al.An immunomodulatory role Fas-mediated apoptosis. Gut 2015;64:1303–13. for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection.He- 69. Tan Z, Qian X, Jiang R, Liu Q, Wang Y, Chen C, et al. IL-17A plays a critical role in patology. 2004;40:1062–71. the pathogenesis of liver ﬁbrosis through hepatic stellate cell activation. J 43. Kondo Y, Kobayashi K, Ueno Y, Shiina M, Niitsuma H, Kanno N, et al. Mechanism Immunol. 2013;191:1835–44. of T cell hyporesponsiveness to HBcAg is associated with regulatory T cells in 70. Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, et al. Interleukin- chronic hepatitis B. World J Gastroenterol. 2006;12:4310–7. 17 signaling in inﬂammatory, Kupffer cells, and hepatic stellate cells exacerbates 44. Bataller R, Lemon SM. Fueling ﬁbrosis in chronic hepatitis C. Proc Natl Acad Sci liver ﬁbrosis in mice. Gastroenterology 2012;143:765–76. e3 USA. 2012;109:14293–4. 71. Zhou W, Yang Y, Mei C, Dong P, Mu S, Wu H, et al. Inhibition of Rho-kinase 45. Nunoya J, Washburn ML, Kovalev GI, Su L. Regulatory T cells prevent liver ﬁbrosis downregulates Th17 cells and ameliorates hepatic ﬁbrosis by Schistosoma during HIV type 1 infection in a humanized mouse model. The. J Infect Dis. japonicum infection. Cells 2019;8:1262. 2014;209:1039–44. 72. Lan YT, Wang ZL, Tian P, Gong XN, Fan YC, Wang K. Treg/Th17 imbalance and its 46. Ikeno Y, Ohara D, Takeuchi Y, Watanabe H, Kondoh G, Taura K, et al. Foxp3+ clinical signiﬁcance in patients with hepatitis B-associated liver cirrhosis. Diagn regulatory T Cells inhibit CCl4-induced liver inﬂammation and ﬁbrosis by reg- Pathol. 2019;14:114. ulating tissue cellular immunity. Front Immunol. 2020;11:584048. 73. Rong G, Zhou Y, Xiong Y, Zhou L, Geng H, Jiang T, et al. Imbalance between T 47. Gu L, Deng WS, Sun XF, Zhou H, Xu Q. Rapamycin ameliorates CCl4-induced liver helper type 17 and T regulatory cells in patients with primary biliary cirrhosis: the ﬁbrosis in mice through reciprocal regulation of the Th17/Treg cell balance. Mol serum cytokine proﬁle and peripheral cell population. Clin Exp Immunol. Med Rep. 2016;14:1153–61. 2009;156:217–25. 48. Huang GC, Zhang JS, Tang QQ. Involvement of C/EBP-alpha gene in in vitro 74. Wang W, Shao S, Jiao Z, Guo M, Xu H, Wang S. The Th17/Treg imbalance and activation of rat hepatic stellate cells. Biochem Biophys Res Commun. cytokine environment in peripheral blood of patients with rheumatoid arthritis. 2004;324:1309–18. Rheumatol Int. 2012;32:887–93. Cell Death Discovery (2023) 9:53 K. Wu et al. 75. Shan J, Jin H, Xu Y. T cell metabolism: a new perspective on Th17/Treg AUTHOR CONTRIBUTIONS cell imbalance in systemic Lupus erythematosus. Front Immunol. 2020;11: Conception and design: KW, QQ, JZ and DS. Data collection: KW and XZ. Writing the 1027. article: KW, QQ, JZ, DS, YD and XZ. Critical revision of the article: XZ, and YL. Final 76. Oukka M. Interplay between pathogenic Th17 and regulatory T cells. Ann Rheum approval of the article: KW, XZ, KS and YL. Statistical analysis: KW, XZ and YD. Dis. 2007;66:iii87–90. Obtained funding: YL and KS. Overall responsibility: YL. All authors contributed to the 77. Zhai S, Zhang L, Dang S, Yu Y, Zhao Z, Zhao W, et al. The ratio of Th-17 to Treg article and approved the submitted version. cells is associated with survival of patients with acute-on-chronic hepatitis B liver failure. Viral Immunol. 2011;24:303–10. 78. Yu X, Guo R, Ming D, Su M, Lin C, Deng Y, et al. Ratios of regulatory T cells/T- FUNDING helper 17 cells and transforming growth factor-β1/interleukin-17 to be associated This work was supported by the National Natural Science Foundation of China with the development of hepatitis B virus-associated liver cirrhosis. J Gastro- (81971504), Changzhou Top Health Talents Project (KY20221374), Jiangsu Science enterol Hepatol. 2014;29:1065–72. and Technology Talent Promotion Project (TJ2022052), Changzhou International 79. Nan XP, Zhang Y, Yu HT, Sun RL, Peng MJ, Li Y, et al. Inhibition of viral replication Science and Technology Cooperation Project (CZ20220032), The lifting Project of downregulates CD4(+)CD25(high) regulatory T cells and programmed death- Young Scientiﬁc and technological talents in Changzhou (KY20211103), Sino-German ligand 1 in chronic hepatitis B. Viral Immunol. 2012;25:21–8. Center Project (GZ1600), Changzhou Society Development Funding (CE20205038), 80. Yang L, Jia S, Shao X, Liu S, Zhang Q, Song J, et al. Interleukin-35 modulates Jiangsu Postdoctoral Talent Project (2020Z021). the balance between viral speciﬁcCD4(+)CD25(+)CD127(dim/-) regulatory T cells and T helper 17 cells in chronic hepatitis B virus infection. Virol J. 2019;16:48. COMPETING INTERESTS 81. Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. The authors declare no competing interests. Immunity 2009;30:646–55. 82. Deknuydt F, Bioley G, Valmori D, Ayyoub M. IL-1beta and IL-2 convert human Treg into T(H)17 cells. Clin Immunol. 2009;131:298–307. 83. Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). ETHICS Ann Rev Immunol. 2010;28:445–89. This study was approved by the Ethics Committee of the Third Afﬁliated Hospital of 84. Mangodt TC, Van Herck MA, Nullens S, Ramet J, De Dooy JJ, Jorens PG, et al. The Soochow University. role of Th17 and Treg responses in the pathogenesis of RSV infection. Pediatr Res. 2015;78:483–91. 85. Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. ADDITIONAL INFORMATION 2010;40:1830–5. Correspondence and requests for materials should be addressed to Xi Zhu or Yun-jie 86. Fujimoto M, Nakano M, Terabe F, Kawahata H, Ohkawara T, Han Y, et al. The Lu. inﬂuence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells. J Immunol. 2011;186:32–40. Reprints and permission information is available at http://www.nature.com/ 87. Lunz JG 3rd, Specht SM, Murase N, Isse K, Demetris AJ. Gut-derived commensal reprints bacterial products inhibit liver dendritic cell maturation by stimulating hepatic interleukin-6/signal transducer and activator of transcription 3 activity. Hepatol- Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims ogy. 2007;46:1946–59. in published maps and institutional afﬁliations. 88. Boveda-Ruiz D, D’Alessandro-Gabazza CN, Toda M, Takagi T, Naito M, Matsushima Y, et al. Differential role of regulatory T cells in early and late stages of pulmonary ﬁbrosis. Immunobiology. 2013;218:245–54. 89. Xu D, Fu J, Jin L, Zhang H, Zhou C, Zou Z, et al. Circulating and liver resident Open Access This article is licensed under a Creative Commons CD4+CD25+ regulatory T cells actively inﬂuence the antiviral immune response Attribution 4.0 International License, which permits use, sharing, and disease progression in patients with hepatitis B. J Immunol. 2006;177: adaptation, distribution and reproduction in any medium or format, as long as you give 739–47. appropriate credit to the original author(s) and the source, provide a link to the Creative 90. Drescher HK, Bartsch LM, Weiskirchen S, Weiskirchen R. Intrahepatic TH17/TReg Commons license, and indicate if changes were made. The images or other third party cells in homeostasis and disease-It’s all about the balance. Front Pharm. material in this article are included in the article’s Creative Commons license, unless 2020;11:588436. indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http:// creativecommons.org/licenses/by/4.0/. ACKNOWLEDGEMENTS We would like to show sincere appreciation to the anonymous reviewers for their many useful comments on the early version of the manuscript. © The Author(s) 2023 Cell Death Discovery (2023) 9:53
Cell Death Discovery – Springer Journals
Published: Feb 9, 2023
Access the full text.
Sign up today, get DeepDyve free for 14 days.