Data_Sheet_1_Regulatory T Cell Extracellular Vesicles Modify T-Effector Cell Cytokine Production and Protect Against Human Skin Allograft Damage.PDF

Regulatory T cells (Tregs) are a subpopulation of CD4+ T cells with a fundamental role in maintaining immune homeostasis and inhibiting unwanted immune responses using several different mechanisms. Recently, the intercellular transfer of molecules between Tregs and their target cells has been shown via trogocytosis and the release of small extracellular vesicles (sEVs). In this study, CD4+CD25+CD127lo human Tregs were found to produce sEVs capable of inhibiting the proliferation of effector T cells (Teffs) in a dose dependent manner. These vesicles also modified the cytokine profile of Teffs leading to an increase in the production of IL-4 and IL-10 whilst simultaneously decreasing the levels of IL-6, IL-2, and IFNγ. MicroRNAs found enriched in the Treg EVs were indirectly linked to the changes in the cytokine profile observed. In a humanized mouse skin transplant model, human Treg derived EVs inhibited alloimmune-mediated skin tissue damage by limiting immune cell infiltration. Taken together, Treg sEVs may represent an exciting cell-free therapy to promote transplant survival.

调节性T细胞（Regulatory T cells, Tregs）是CD4阳性T细胞的一个亚群，在维持免疫稳态、通过多种不同机制抑制异常免疫应答方面发挥着基础性作用。近期研究通过胞啃作用（trogocytosis）以及小型细胞外囊泡（small extracellular vesicles, sEVs）的释放，证实了Tregs与其靶细胞之间可发生分子的细胞间转移。本研究发现，CD4+CD25+CD127lo 人源Tregs能够分泌可呈剂量依赖性抑制效应T细胞（effector T cells, Teffs）增殖的sEVs。这些囊泡还可重塑效应T细胞的细胞因子谱：促进IL-4与IL-10的产生，同时降低IL-6、IL-2及IFNγ的表达水平。富集于Treg来源囊泡中的微小RNA（MicroRNAs）与上述观测到的细胞因子谱变化存在间接关联。在人源化小鼠皮肤移植模型中，人源Treg衍生的sEVs可通过限制免疫细胞浸润，抑制同种免疫介导的皮肤组织损伤。综上，Treg来源的sEVs有望成为一种极具潜力的无细胞疗法，用于提升移植存活率。