Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Department of Electrical Engineering and Computer Sciences and Center for Computational Biology, UC Berkeley, Berkeley, CA 94720, USA.
Immunity. 2022 Sep 13;55(9):1663-1679.e6. doi: 10.1016/j.immuni.2022.08.007. Epub 2022 Sep 6.
Interleukin-23 receptor plays a critical role in inducing inflammation and autoimmunity. Here, we report that Th1-like cells differentiated in vitro with IL-12 + IL-21 showed similar IL-23R expression to that of pathogenic Th17 cells using eGFP reporter mice. Fate mapping established that these cells did not transition through a Th17 cell state prior to becoming Th1-like cells, and we observed their emergence in vivo in the T cell adoptive transfer colitis model. Using IL-23R-deficient Th1-like cells, we demonstrated that IL-23R was required for the development of a highly colitogenic phenotype. Single-cell RNA sequencing analysis of intestinal T cells identified IL-23R-dependent genes in Th1-like cells that differed from those expressed in Th17 cells. The perturbation of one of these regulators (CD160) in Th1-like cells inhibited the induction of colitis. We thus uncouple IL-23R as a purely Th17 cell-specific factor and implicate IL-23R signaling as a pathogenic driver in Th1-like cells inducing tissue inflammation.
白细胞介素-23 受体在诱导炎症和自身免疫中起着关键作用。在这里，我们报告说，使用 eGFP 报告小鼠，在用 IL-12+IL-21 体外分化的 Th1 样细胞中观察到与致病性 Th17 细胞相似的 IL-23R 表达。命运图谱建立表明，这些细胞在成为 Th1 样细胞之前没有通过 Th17 细胞状态过渡，并且我们在 T 细胞过继转移结肠炎模型中观察到它们在体内的出现。使用 IL-23R 缺陷型 Th1 样细胞，我们证明 IL-23R 是高度致结肠炎表型发展所必需的。对肠道 T 细胞的单细胞 RNA 测序分析鉴定了 Th1 样细胞中依赖于 IL-23R 的基因，这些基因与 Th17 细胞中表达的基因不同。在 Th1 样细胞中干扰其中一个调节剂（CD160）抑制了结肠炎的诱导。因此，我们将 IL-23R 与 Th17 细胞特异性因子分离，并表明 IL-23R 信号在诱导组织炎症的 Th1 样细胞中是一种致病驱动因素。
