Molecular and functional heterogeneity of IL-10-producing CD4+ T cells [Human 10x]. Molecular and functional heterogeneity of IL-10-producing CD4+ T cells [Human 10x]

IL-10 is a prototypical anti-inflammatory cytokine, which is fundamental to the maintenance of immune homeostasis, especially in the intestine. There is an assumption that cells producing IL-10 have an immunoregulatory function. However, here we report that IL-10-producing CD4+ T cells are phenotypically and functionally heterogeneous. By combining single cell transcriptome and functional analyses, we identified a subpopulation of IL-10-producing Foxp3Neg CD4+ T cells that displays regulatory activity unlike other IL-10-producing CD4+ T cells, which are unexpectedly pro-inflammatory. The combinatorial expression of co-inhibitory receptors is sufficient to discriminate IL-10-producing CD4+ T cells with regulatory function from others and to identify them across different tissues and disease models in mice and humans. These regulatory IL-10-producing Foxp3Neg CD4+ T cells have a unique transcriptional program, which goes beyond the regulation of IL-10 expression. Finally, we found that patients with Inflammatory Bowel Disease (IBD), demonstrate a deficiency in this specific regulatory T-cell subpopulation. Overall design: We performed scRNA-seq analysis of IL-10-producing CD4+ T cells isolated from the blood (PBMCs) of two healthy donors

白介素10（IL-10）是典型的抗炎细胞因子，对维持免疫稳态至关重要，尤其在肠道环境中。此前学界普遍认为，分泌IL-10的细胞具备免疫调节功能。然而本研究证实，分泌IL-10的CD4阳性T细胞（CD4+ T cells）存在表型与功能异质性。通过联合单细胞转录组与功能分析，我们鉴定出一类分泌IL-10的Foxp3阴性（Foxp3Neg）CD4阳性T细胞亚群：与其他分泌IL-10的CD4阳性T细胞不同，该亚群展现出调节活性，而其余亚群竟具有促炎特性。共抑制受体的组合表达足以区分具有调节功能的分泌IL-10 CD4阳性T细胞与其他同类细胞，并可在小鼠与人类的不同组织及疾病模型中识别该亚群。这类具有调节功能的分泌IL-10 Foxp3阴性CD4阳性T细胞拥有独特的转录调控程序，其调控范畴远超IL-10的表达调控。最后我们发现，炎症性肠病（Inflammatory Bowel Disease, IBD）患者体内，该特异性调节性T细胞亚群存在数量缺失。整体实验设计：我们对两名健康供者外周血单个核细胞（PBMCs）中分离得到的分泌IL-10的CD4阳性T细胞开展了单细胞RNA测序（scRNA-seq）分析。