The neonatal microenvironment programs innate γδ T cells through the transcription factor STAT5
The neonatal microenvironment programs innate γδ T cells through the transcription factor STAT5
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DOI：
10.1172/jci131241
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发表时间：
2020-05-01
影响因子：
15.9
通讯作者：
Bekiaris, Vasileios
中科院分区：
文献类型：
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作者：
Kadekar, Darshana;Agerholm, Rasmus;Bekiaris, Vasileios
产生IL-17的ROR γ t（+）γ δ T细胞（γ δ T17细胞）是在感染和炎症期间参与3型免疫应答的先天性淋巴细胞。在此，我们发现γ δ T17细胞在新生儿淋巴结和肠道内迅速增殖，在进入后，它们以STAT 3和视黄酸依赖性方式上调T-bet并共表达IL-17、IL-22和IFN-γ。在STAT 5有条件缺陷的小鼠中，新生儿扩增停止，其损失导致所有成年器官中的γ δ T17细胞耗竭。过度活跃的STAT 5突变小鼠显示，STAT 5A同源物在促进γ δ T17细胞扩增和下调肠道相关T-bet方面具有超过STAT 5 B的主导作用。相比之下，STAT 5 B优先扩增产生IFN-γ的γ-δ群体，这意味着STAT 5基因产物在淋巴细胞谱系调节中的先前未知的差异作用。重要的是，由于STAT 5缺乏而缺乏γ δ T17细胞的小鼠显示出对实验性自身免疫性脑脊髓炎的深刻抵抗。我们的数据表明，新生儿微环境与STAT 5的结合对于胸腺后γ δ T17发育和组织特异性印迹至关重要，这对感染和自身免疫至关重要。
IL-17-producing ROR gamma t(+) gamma delta T cells (gamma delta T17 cells) are innate lymphocytes that participate in type 3 immune responses during infection and inflammation. Herein, we show that gamma delta T17 cells rapidly proliferate within neonatal lymph nodes and gut, where, upon entry, they upregulate T-bet and coexpress IL-17, IL-22, and IFN-gamma in a STAT3- and retinoic acid-dependent manner. Neonatal expansion was halted in mice conditionally deficient in STAT5, and its loss resulted in gamma delta T17 cell depletion from all adult organs. Hyperactive STAT5 mutant mice showed that the STAT5A homolog had a dominant role over STAT5B in promoting gamma delta T17 cell expansion and downregulating gut-associated T-bet. In contrast, STAT5B preferentially expanded IFN-gamma-producing gamma delta populations, implying a previously unknown differential role of STAT5 gene products in lymphocyte lineage regulation. Importantly, mice lacking gamma delta T17 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 gamma delta T17 development and tissue-specific imprinting, which is essential for infection and autoimmunity.