CD4+ Primary T Cells Expressing HCV-Core Protein Upregulate Foxp3 and IL-10, Suppressing CD4 and CD8 T Cells

Abstract

Adaptive T cell responses are critical for controlling HCV infection. While there is clinical evidence of a relevant role for regulatory T cells in chronic HCV-infected patients, based on their increased number and function; mechanisms underlying such a phenomena are still poorly understood. Accumulating evidence suggests that proteins from Hepatitis C virus can suppress host immune responses. We and others have shown that HCV is present in CD4+ lymphocytes from chronically infected patients and that HCV-core protein induces a state of unresponsiveness in the CD4+ tumor cell line Jurkat. Here we show that CD4+ primary T cells lentivirally transduced with HCV-core, not only acquire an anergic phenotype but also inhibit IL-2 production and proliferation of bystander CD4+ or CD8+ T cells in response to anti-CD3 plus anti-CD28 stimulation. Core-transduced CD4+ T cells show a phenotype characterized by an increased basal secretion of the regulatory cytokine IL-10, a decreased IFN-γ production upon stimulation, as well as expression of regulatory T cell markers, CTLA-4, and Foxp3. A significant induction of CD4+CD25+CD127lowPD-1highTIM-3high regulatory T cells with an exhausted phenotype was also observed. Moreover, CCR7 expression decreased in HCV-core expressing CD4+ T cells explaining their sequestration in inflamed tissues such as the infected liver. This work provides a new perspective on de novo generation of regulatory CD4+ T cells in the periphery, induced by the expression of a single viral protein.

Hepatitis C virus core protein triggers expansion and activation of CD4+CD25+ regulatory T cells in chronic hepatitis C patients

“…6,12,19 An effect of HCV core expression on CD4 1 T cells has been reported, showing that this protein induces a state of unresponsiveness similar to clonal anergy or T-cell exhaustion. [20][21][22] HCVc can bind the human complement receptor C1qR, thus inhibiting T-cell responses. 23,24 More recently, using a lentiviral vector to express HCVc in CD4 1 Jurkat T cells, Dominguez-Villar et al 25 report that FoxP3 and CTLA-4 (cytotoxic T-lymphocyte antigen-4) were upregulated in HCVc-expressing Jurkat cells and that HCVc-transfected Jurkat cells were able to suppress CD4 1 and CD8 1 T-cell responses to anti-CD3 plus anti-CD28 stimulation.…”

Immune checkpoint inhibition: prospects for prevention and therapy of hepatocellular carcinoma

“…Interestingly, though, there are some patients whose HCV‐specific T cells are only weakly primed during the acute infection phase 75 . Hepatitis C‐infected patients also have increased numbers of CD4 + T reg cells, possibly as a result of the HCV core protein inducing a T reg ‐like phenotype expressing the T reg transcription factor Foxp3, together with immunosuppressive IL‐10 76 …”

“…75 Hepatitis C-infected patients also have increased numbers of CD4 + T reg cells, possibly as a result of the HCV core protein inducing a T reg -like phenotype expressing the T reg transcription factor Foxp3, together with immunosuppressive IL-10. 76 The mechanisms by which CD8 + T cells become exhausted and/or deleted during viral infection are not completely understood. However, there are several mechanisms in addition to CD4 + T-cell dysfunction that may result in CD8 + T-cell exhaustion.…”

Immune modulation by the hepatitis C virus core protein

“…HCV core induction of CD4 + CD25 + CD127 low PD1 high TIM3 high regulatory T cells with an exhausted phenotype and decreased CCR7 expression was also described. The CCR7 diminished expression levels explain the HCV core‐induced Treg cell sequestration in inflamed tissues, such as the infected liver …”