Mycophenolic acid-treated dendritic cells generate regulatory CD4+ T cells that suppress CD8+ T cells' allocytotoxicity.
Regulatory T cells (Treg) play a crucial role in controlling immunity and transplant rejection. Two main groups of Treg have been described: antigen-induced Treg (iTreg) and natural Treg (nTreg). The ways to induce and the mechanisms of action of Treg subsets remained ill defined, particularly for their effects on CD8(+) T cells. CD8(+) T cells are major agents in the rejection of allografts; the aim of this study is to investigate the effects exerted on CD8(+) T cells by human CD4(+) iTreg induced by mycophenolic acid-treated dendritic cells. iTreg suppress the proliferation of CD8(+) T cells by allogeneic cell-cell interaction with mature dendritic cells and irrespectively of the TCR specificity of the CD8(+) T cells and cell-cell contact of iTreg with CD8(+) T cells. In our model, this suppression is independent of the action of IL-10 and TGF-β1. iTreg were able to modify phenotype and inhibited IFN-γ and TNF-α secretion by CD8(+) T cells. Most interestingly, iTreg inhibit the synthesis of perforin and of granzymes A and B by CD8(+) T cells and impaired their cytotoxicity against allogeneic targets. In summary, our study showed the involvement of iTreg in the down-regulation of cytotoxic responses mediated by CD8(+) T cells in an allospecific context. Following studies that have shown the existence of a regulation control exerted by iTreg on CD4(+) T cells and dendritic cells, this work ultimately shows that this regulation can reach CD8(+) T-cell functions.
UPRES EA 4245 « Cellules Dendritiques, Immunomodulation et Greffes », UFR de Médecine, Université François-Rabelais, 10 Boulevard Tonnellé, 37000 Tours, France.
Ihab
I
Kazma
Roxane
R
Lemoine
Florence
F
Herr
Stephanie
S
Chadet
Daniel
D
Meley
Florence
F
Velge-Roussel
Yvon
Y
Lebranchu
Christophe
C
Baron
D015704:CD4 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D053804:Granzymes; D006801:Humans; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D009173:Mycophenolic Acid / Q000494:pharmacology*; D054353:Perforin / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014181:Transplantation Immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015704:CD4 Antigens; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes; D009173:Mycophenolic Acid
cytotoxicity; immune regulation; organ transplantation