Kazma Ihab, Lemoine Roxane, Herr Florence, Chadet Stephanie, Meley Daniel, Velge-Roussel Florence, Lebranchu Yvon, Baron Christophe
UPRES EA 4245 « Cellules Dendritiques, Immunomodulation et Greffes », UFR de Médecine, Université François-Rabelais, 10 Boulevard Tonnellé, 37000 Tours, France.
Int Immunol. 2014 Mar;26(3):173-81. doi: 10.1093/intimm/dxt054. Epub 2013 Nov 12.
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.
调节性T细胞（Treg）在控制免疫和移植排斥中发挥着关键作用。已描述了两类主要的Treg：抗原诱导的Treg（iTreg）和天然Treg（nTreg）。Treg亚群的诱导方式和作用机制仍不明确，尤其是它们对CD8(+) T细胞的影响。CD8(+) T细胞是同种异体移植物排斥的主要介质；本研究的目的是探讨经霉酚酸处理的树突状细胞诱导的人CD4(+) iTreg对CD8(+) T细胞的影响。iTreg通过与成熟树突状细胞的同种异体细胞间相互作用抑制CD8(+) T细胞的增殖，且与CD8(+) T细胞的TCR特异性以及iTreg与CD8(+) T细胞的细胞间接触无关。在我们的模型中，这种抑制作用独立于IL-10和TGF-β1的作用。iTreg能够改变CD8(+) T细胞的表型并抑制其IFN-γ和TNF-α分泌。最有趣的是，iTreg抑制CD8(+) T细胞中穿孔素、颗粒酶A和颗粒酶B的合成，并削弱其对同种异体靶标的细胞毒性。总之，我们的研究表明iTreg在同种异体特异性背景下参与下调由CD8(+) T细胞介导地细胞毒性反应。在已表明iTreg对CD4(+) T细胞和树突状细胞存在调节控制作用的后续研究之后，这项工作最终表明这种调节作用可以影响CD8(+) T细胞的功能。
