Core-specific adaptive regulatory T cells in different outcomes of hepatitis C

Bettina Langhans (1) , Ingrid Braunschweiger , Simone Arndt , Wibke Schulte , Judith Satoguina , Laura E Layland , Natascha Vidovic , Achim Hoerauf , Johannes Oldenburg , Tilman Sauerbruch , Ulrich Spengler

1 Department of Internal Medicine I

Background: CD4+ regulatory T cells (Tregs) probably contribute to the impaired virus-specific T cell responses in chronic hepatitis C virus (HCV) infection. However, their antigen-specificity has remained elusive. Methods: We analyzed peripheral blood CD4+ Tregs in patients with chronic and self-limited HCV infection and characterized individual Treg clones obtained from both patient groups at the phenotypic and functional level. Results: Foxp3+CD25+CD4+ Tregs were detected more frequently in patients with chronic than self-limited HCV infection, which responded to HCV core stimulation and inhibited proliferation of reporter cells. Cloning under limiting dilution conditions resulted in fourteen and six hypoproliferative Foxp3+CD25+CD127-CD4+ T cell clones from patients with chronic and self-limited HCV infection, respectively. All clones expressed Treg markers and produced IL-10 upon mitogen stimulation. However, exclusively Treg clones from chronic hepatitis C produced IL-10 in response to HCV core and inhibited proliferation of reporter T cells. These core-specific Treg clones recognized epitopes in two regions of HCV core (aa1-44 and aa79-113). Co-culture inhibition assays demonstrated Tregs to inhibit reporter T cells via secretion of IL-10 and IL-35 rather than cell-contact-dependent mechanisms. Finally, the HCV-specific Treg clones lost their functional capacity along with Foxp3 expression, if kept in culture without HCV core exposure. Conclusions: We identified functionally active HCV core-specific Tregs in patients with chronic hepatitis C, which share their epitopes with conventional T cells and require the continued presence of antigen to maintain their functional differentiation. Thus, HCV core-specific Tregs may contribute to the immunoregulatory balance in chronic hepatitis C.

Mots clés: Medicine

Bettina Langhans, Ingrid Braunschweiger, Simone Arndt, Wibke Schulte, Judith Satoguina, et al.. Core-specific adaptive regulatory T cells in different outcomes of hepatitis C. Clinical Science, 2010, 119 (2), pp.97-109. ⟨10.1042/CS20090661⟩. ⟨hal-00587269⟩