Bézie Séverine, Meistermann Dimitri, Boucault Laetitia, Kilens Stéphanie, Zoppi Johanna, Autrusseau Elodie, Donnart Audrey, Nerrière-Daguin Véronique, Bellier-Waast Frédérique, Charpentier Eric, Duteille Franck, David Laurent, Anegon Ignacio, Guillonneau Carole
Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.
Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
Front Immunol. 2018 Jan 31;8:2014. doi: 10.3389/fimmu.2017.02014. eCollection 2017.
Both CD4 and CD8 Tregs play a critical role in the control of immune responses and immune tolerance; however, our understanding of CD8 Tregs is limited while they are particularly promising for therapeutic application. We report here existence of highly suppressive human CD8CD45RC Tregs expressing Foxp3 and producing IFNγ, IL-10, IL-34, and TGFβ to mediate their suppressive activity. We demonstrate that total CD8CD45RC Tregs can be efficiently expanded in the presence of anti-CD3/28 mAbs, high-dose IL-2 and IL-15 and that such expanded Tregs efficiently delay GVHD and human skin transplantation rejection in immune humanized mice. Robustly expanded CD8 Tregs displayed a specific gene signature, upregulated cytokines and expansion in the presence of rapamycin greatly improved proliferation and suppression. We show that CD8CD45RC Tregs are equivalent to canonical CD4CD25CD127 Tregs for suppression of allogeneic immune responses . Altogether, our results open new perspectives to tolerogenic strategies in human solid organ transplantation and GVHD.
CD4和CD8调节性T细胞（Tregs）在免疫反应控制和免疫耐受中均发挥关键作用；然而，我们对CD8 Tregs的了解有限，尽管它们在治疗应用方面前景尤为广阔。我们在此报告，存在高抑制性的人类CD8CD45RC Tregs，其表达Foxp3并产生IFNγ、IL-10、IL-34和TGFβ以介导其抑制活性。我们证明，在抗CD3/28单克隆抗体、高剂量IL-2和IL-15存在的情况下，总CD8CD45RC Tregs能够有效扩增，且这种扩增的Tregs能有效延缓免疫人源化小鼠的移植物抗宿主病（GVHD）和人类皮肤移植排斥反应。强力扩增的CD8 Tregs表现出特定的基因特征，上调的细胞因子以及在雷帕霉素存在下的扩增极大地改善了增殖和抑制作用。我们表明，CD8CD45RC Tregs在抑制同种异体免疫反应方面等同于典型的CD4CD25CD127 Tregs。总之，我们的结果为人类实体器官移植和GVHD的耐受性策略开辟了新的前景。
