Abstract
Hepatitis C infection induces an acute and chronic liver inflammation that may lead to cirrhosis, liver failure, or hepatocarcinoma. Since the role of alphabeta T lymphocytes in hepatitis C virus (HCV) immunopathology has been analyzed extensively, we investigated the distribution and functional activation of gammadelta T cell subsets in chronically HCV-infected patients. Blood samples and liver biopsies from 35 patients with compensated chronic HCV infection were compared in terms of T cell subset distribution, expression of activation markers, gammadelta T cell receptor (TCR) repertoire, and pattern of cytokine production. Moreover, we analyzed whether these immunological parameters were associated with other clinical observations (plasma viremia, ALT levels, Ishak index). Differing from peripheral blood distribution, a specific compartmentalization of Vdelta1 T cells (p < 0.001) was observed in the liver of HCV patients. These cells represented a relevant fraction of intrahepatic T lymphocytes (1.8-8.7%) and expressed the memory/effector phenotype (CD62-L- CD45-RO+CD95+). This phenotype was consistent with selective homing upon antigen recognition. Mitogenic stimulation of Vdelta1 + T lymphocytes recruited in the liver revealed the T helper cell type 1 (Th1) pattern of cytokine secretion. Interestingly, the frequency of interferon-gamma (IFN-gamma)-producing Vdelta1 T cells was associated with an higher degree of liver necroinflammation, measured by the Ishak index. Finally, the T-cell repertoire analysis revealed the absence of Vgamma selection in the TCR repertoire of intrahepatic Vdelta1 T cells. gammadelta T cell distribution in the peripheral blood differs from the Vdelta1 T cell subset because it is policlonally activated and recruited in the liver of chronic HCV-infected patients. During HCV-infection, this T cell subset may release Th1 cytokines and contribute to the necroinflammatory liver disease.
Highlights
Among hepatitis viruses, hepatitis C virus (HCV) is the main factor responsible for chronic liver disease often progressing to cirrhosis and/or hepatocellular carcinoma [1,2]
␥␦ T lymphocytes represent a minor population of human peripheral lymphocytes, recent studies have demonstrated a predominant localization of lymphocytes expressing the ␥␦ T cell receptors (TCR) in the liver [6,7,8]
Consistent with a functional recruitment of activated T cells, the increase of memory Intrahepatic Lymphocytes (IHL) was paralleled by an induction of human leucocyte antigen-DR (HLA-DR) on T lymphocytes (Fig. 1F)
Summary
Hepatitis C virus (HCV) is the main factor responsible for chronic liver disease often progressing to cirrhosis and/or hepatocellular carcinoma [1,2]. Since the role of ␣ T lymphocytes in hepatitis C virus (HCV) immunopathology has been analyzed extensively, we investigated the distribution and functional activation of ␥␦ T cell subsets in chronically HCV-infected patients. Materials and Methods: Blood samples and liver biopsies from 35 patients with compensated chronic HCV infection were compared in terms of T cell subset distribution, expression of activation markers, ␥␦ T cell receptor (TCR) repertoire, and pattern of cytokine production. Results: Differing from peripheral blood distribution, a specific compartmentalization of V␦1 T cells (p Ͻ 0.001) was observed in the liver of HCV patients These cells represented a relevant fraction of intrahepatic T lymphocytes (1.8–8.7%) and expressed the memory/effector phenotype (CD62-LϪ CD45-ROϩCD95ϩ). Conclusions: ␥␦ T cell distribution in the peripheral blood differs from the V␦1 T cell subset because it is policlonally activated and recruited in the liver of chronic HCV-infected patients. During HCV-infection, this T cell subset may release Th1 cytokines and contribute to the necroinflammatory liver disease
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