CD4+ primary T cells expressing HCV-core protein upregulate Foxp3 and IL-10, suppressing CD4 and CD8 T cells.
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+CD127(low)PD-1(high)TIM-3(high) 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.
Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain.
Cecilia
C
Fernandez-Ponce
Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain.
Margarita
M
Dominguez-Villar
Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain.
Enrique
E
Aguado
Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain.
Francisco
F
Garcia-Cozar
D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D016174:Hepacivirus / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D014758:Viral Core Proteins / Q000378:metabolism*
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D014758:Viral Core Proteins; D016753:Interleukin-10