Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark.
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
J Clin Invest. 2020 May 1;130(5):2496-2508. doi: 10.1172/JCI131241.
IL-17-producing RORγt+ γδ T cells (γδT17 cells) are innate lymphocytes that participate in type 3 immune responses during infection and inflammation. Herein, we show that γδT17 cells rapidly proliferate within neonatal lymph nodes and gut, where, upon entry, they upregulate T-bet and coexpress IL-17, IL-22, and IFN-γ in a STAT3- and retinoic acid-dependent manner. Neonatal expansion was halted in mice conditionally deficient in STAT5, and its loss resulted in γδT17 cell depletion from all adult organs. Hyperactive STAT5 mutant mice showed that the STAT5A homolog had a dominant role over STAT5B in promoting γδT17 cell expansion and downregulating gut-associated T-bet. In contrast, STAT5B preferentially expanded IFN-γ-producing γδ populations, implying a previously unknown differential role of STAT5 gene products in lymphocyte lineage regulation. Importantly, mice lacking γδT17 cells as a result of STAT5 deficiency displayed a profound resistance to experimental autoimmune encephalomyelitis. Our data identify that the neonatal microenvironment in combination with STAT5 is critical for post-thymic γδT17 development and tissue-specific imprinting, which is essential for infection and autoimmunity.
IL-17 产生的 RORγt+γδT 细胞（γδT17 细胞）是先天淋巴细胞，它们在感染和炎症期间参与 3 型免疫反应。在此，我们表明 γδT17 细胞在新生儿淋巴结和肠道中迅速增殖，进入后，它们以 STAT3 和视黄酸依赖的方式上调 T-bet 并共同表达 IL-17、IL-22 和 IFN-γ。条件性缺乏 STAT5 的小鼠中，新生儿扩增被阻断，其缺失导致所有成年器官中 γδT17 细胞耗竭。STAT5 超活性突变小鼠表明，STAT5A 同源物在促进 γδT17 细胞扩增和下调肠道相关 T-bet 方面比 STAT5B 具有优势。相比之下，STAT5B 优先扩增产生 IFN-γ 的 γδ 群体，这意味着 STAT5 基因产物在淋巴细胞谱系调节中的作用以前是未知的。重要的是，由于 STAT5 缺乏导致的 γδT17 细胞缺失的小鼠对实验性自身免疫性脑脊髓炎表现出明显的抗性。我们的数据表明，新生儿微环境与 STAT5 一起对于胸腺后 γδT17 细胞的发育和组织特异性印记至关重要，这对于感染和自身免疫是必需的。
