The neonatal microenvironment programs innate γδ T cells through the transcription factor STAT5.

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.