The neonatal microenvironment programs conventional and intestinal Tbet+ γδT17 cells through the transcription factor STAT5

Interleukin(IL)-17-producing RORγt+ γδ T (γδT17) cells develop in the embryonic thymus and participate in type 3 immune responses. Herein we show that γδT17 cells rapidly proliferate within neonatal lymph nodes and gut, where upon entry they uniquely upregulate Tbet and co-express IL-17, IL-22 and interferon (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 homologue had a dominant role over STAT5B in promoting γδT17 cell expansion and downregulating gut-associated Tbet. In contrast, STAT5B preferentially expanded IFNγ-producing γδ populations. Importantly, mice lacking γδT17 cells due to STAT5 deficiency displayed a profound resistance to experimental autoimmune encephalomyelitis. Our data identify for the first time STAT5 as a key molecular checkpoint allowing γδT17 cells to pass through a critical neonatal developmental window to acquire tissue-specific characteristics essential for infection and autoimmunity.