1. Mycophenolic acid-treated dendritic cells generate regulatory CD4+ T cells that suppress CD8+ T cells' allocytotoxicity.
- Author
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Kazma I, Lemoine R, Herr F, Chadet S, Meley D, Velge-Roussel F, Lebranchu Y, and Baron C
- Subjects
- CD4 Antigens metabolism, Cell Communication, Cell Differentiation, Cells, Cultured, Coculture Techniques, Cytotoxicity, Immunologic, Dendritic Cells immunology, Granzymes, Humans, Immunosuppression Therapy, Interferon-gamma metabolism, Lymphocyte Activation, Perforin metabolism, T-Cell Antigen Receptor Specificity immunology, Transplantation Immunology, Tumor Necrosis Factor-alpha metabolism, CD8-Positive T-Lymphocytes immunology, Dendritic Cells drug effects, Mycophenolic Acid pharmacology, T-Lymphocyte Subsets immunology, T-Lymphocytes, Regulatory immunology
- Abstract
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.
- Published
- 2014
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