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bioRxiv · 10.1101/658542

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

Kadekar, D.·Agerholm, R.·Rizk, J.·Neubauer, H.·Suske, T.·Maurer, B.·Vinals, M. T.·Comelli, E.·Taibi, A.·Moriggl, R.·Bekiaris, V.
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Abstract

Interleukin(IL)-17-producing ROR{gamma}t+ {gamma}{delta} T ({gamma}{delta}T17) cells develop in the embryonic thymus and participate in type 3 immune responses. Herein we show that {gamma}{delta}T17 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) {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 homologue had a dominant role over STAT5B in promoting {gamma}{delta}T17 cell expansion and downregulating gut-associated Tbet. In contrast, STAT5B preferentially expanded IFN{gamma}-producing {gamma}{delta} populations. Importantly, mice lacking {gamma}{delta}T17 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 {gamma}{delta}T17 cells to pass through a critical neonatal developmental window to acquire tissue-specific characteristics essential for infection and autoimmunity.

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Kadekar, D., Agerholm, R., Rizk, J., Neubauer, H., Suske, T., Maurer, B., Vinals, M. T., Comelli, E., Taibi, A., Moriggl, R., Bekiaris, V.. 2019-06-03. The neonatal microenvironment programs conventional and intestinal Tbet+ γδT17 cells through the transcription factor STAT5. https://doi.org/10.1101/658542

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