5-8 It is likely that in chronic infection, persistence of inefficient effector T-cell responses cause collateral tissue damage and inflammatory reactions, leading to fibrosis and finally cirrhosis. Regulatory/immunosuppressive T cells (Tregs) are apparently involved in HCV pathogenesis, although it remains largely unclear whether

they play a detrimental role by suppressing effector T-cell Torin 1 nmr responses against HCV or are protective by preventing excessive immunological liver damage. Tregs consist of heterogeneous populations that can be natural or induced, antigen-specific or not. Natural Treg, at least in vitro, function via antigen-independent, contact-dependent, and cytokine-independent mechanisms,9

whereas cytokine-mediated suppression (mostly check details interleukin [IL]-10 and/or transforming growth factor beta [TGFβ]) has been established for peripheral adaptive Treg in vivo.10 This heterogeneity leads to ambiguous marker(s) for identifying Tregs. Current optimal Treg markers are expression of Foxp3 (forkhead box p3), a transcription factor,11 high levels of CD25 (although both of these markers can also be expressed by activated effector T cells), as well as minimal CD127 (IL-7 receptor) expression.12 In HCV infection, increased circulating CD4+CD25+Foxp3+ T cells were associated with viral persistence13, 14 with suppressive activity independent of cytokines and antigen nonspecific.15, 16 Histological costaining of liver infiltrates showed CD4+Foxp3+ cells at high proportion in livers of CHC patients,17 suggesting their involvement in intrahepatic immune regulation, but possibly also amelioration of fibrosis.18 HCV can prime virus-specific CD4+CD25+Foxp3+ Treg with antigen-specific expansion and suppression of HCV-specific CD8+ T cells.19 Tregs also include IL-10-producing CD4+ HCV-specific T cells,20 and IL-10 dampens hepatic inflammation, but also leads to increased viral load.21 Peripheral CD4+CD25+ Tregs 上海皓元医药股份有限公司 were shown to secrete TGFβ in response to HCV, which was inversely correlated with liver

inflammation.22 Suppressive IL-10 producing HCV-specific CD8+ liver infiltrating lymphocytes were also described23 and have been associated with protection against apoptosis and fibrosis-related laminin production, as CD8 T cells were located in liver areas with both low hepatocyte apoptosis and fibrosis.24 A limitation of previous studies on Treg is use of phenotypic markers to characterize Treg before functional analysis, as opposed to functionally defining relevant Treg first, so as to not miss subsets. We identified in CHC novel blood HCV-specific CD8+CD25-Foxp3− Treg secreting TGFβ, first functionally then phenotypically.25 TGFβ production by CD4+ T cells was also observed in one patient. Suppression of peripheral HCV-specific IFNγ was predominantly mediated by TGFβ rather than IL-10.