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

Darshana Kadekar, Rasmus Agerholm, John Rizk, Heidi A. Neubauer, Tobias Suske, Barbara Maurer, Monica Torrellas Viñals, Elena M. Comelli, Amel Taibi, Richard Moriggl, Vasileios Bekiaris*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

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Abstract

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.

Original languageEnglish
JournalJournal of clinical investigation
Volume130
Issue number5
Pages (from-to)2496-2508
ISSN0021-9738
DOIs
Publication statusPublished - 2020

Bibliographical note

Funding Information:
We thank John O’Shea (NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA) and Stephen Shoenberger (La Jolla Institute for Immunology, La Jolla, California, USA) for critically reading the manuscript and Immo Prinz (University of Hanover, Hanover, Germany) for providing us with the Vγ6 antibody (17D1). This work, and VB and DK specifically, were supported by Lundbeck Foundation grant R163-2013-15201. DK was additionally supported by LEO Foundation grant LF16020. JR and RA were supported by Technical University of Denmark PhD scholarships. RM, HAN, TS, and BM were supported by the Austrian Science Fund (FWF) (SFB-F04707, SFB-F06105, and under the frame of ERA PerMed [I 4218-B] and ERA-NET [I 4157-B]). RM and HAN were also generously supported by a private cancer metabolism grant donation from Liechtenstein. EMC was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery grant. EMC holds the Lawson Family Chair in Microbiome Nutrition Research at the University of Toronto.

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