Core-specific adaptive regulatory T-cells in different outcomes of hepatitis C.
CD4+ Treg-cells (regulatory T-cells) probably contribute to the impaired virus-specific T-cell responses in chronic HCV (hepatitis C virus) infection; however, their antigen-specificity has remained elusive. In the present study, we analysed peripheral blood CD4+ Treg-cells in patients with chronic hepatitis C and subjects with self-limited HCV infection and characterized individual Treg-cell clones obtained from both groups at the phenotypic and functional level. Foxp3 (forkhead box p3)+CD25+CD4+ Treg-cells were detected more frequently in patients with chronic hepatitis C than self-limited HCV infection, which responded to HCV core stimulation and inhibited proliferation of reporter cells. Cloning under limiting dilution conditions resulted in 14 and six hypoproliferative Foxp3+CD25+CD127-CD4+ T-cell clones from patients with chronic hepatitis C and subjects with self-limited HCV infection respectively. All clones expressed Treg-cell markers and produced IL (interleukin)-10 upon mitogen stimulation. However, exclusively Treg-cell clones from chronic hepatitis C produced IL-10 in response to HCV core and inhibited proliferation of reporter T-cells. These core-specific Treg-cell clones recognized epitopes in two regions of HCV core (amino acids 1-44 and 79-113). Co-culture inhibition assays demonstrated Treg-cells to inhibit reporter T-cells via secretion of IL-10 and IL-35 rather than cell-contact-dependent mechanisms. Finally, the HCV-specific Treg-cell clones lost their functional capacity, along with Foxp3 expression, if kept in culture without HCV core exposure. In conclusion, we identified functionally active HCV core-specific Treg-cells 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 Treg-cells may contribute to the immunoregulatory balance in chronic hepatitis C.
Langhans
Bettina
B
Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. bettina.langhans@ukb.uni-bonn.de
Braunschweiger
Ingrid
I
Arndt
Simone
S
Schulte
Wibke
W
Satoguina
Judith
J
Layland
Laura E
LE
Vidovic
Natascha
N
Hoerauf
Achim
A
Oldenburg
Johannes
J
Sauerbruch
Tilman
T
Spengler
Ulrich
U
D056704:Adaptive Immunity / Q000276:immunology; D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D002478:Cells, Cultured; D002999:Clone Cells / Q000276:immunology; D018920:Coculture Techniques; D018984:Epitopes, T-Lymphocyte / Q000032:analysis; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019562:Viral Load
D018984:Epitopes, T-Lymphocyte; D016753:Interleukin-10