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
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
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Research Article Immunology

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

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.

Authors

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

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Figure 6

STAT5 is a critical determinant of T-bet–expressing intestinal γδT17 cells.

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STAT5 is a critical determinant of T-bet–expressing intestinal γδT17 cel...
Flow cytometric analysis of intestinal γδ T cells in RORγtCRE-STAT5F/F (Cre+) and littermate control mice (Cre−) or in hyperactive STAT5A and STAT5B mutant mice as described in Figure 2. In graphs, each symbol represents a mouse, and lines represent the median. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 using Mann-Whitney test (A–C) or ordinary 1-way ANOVA with Tukey’s multiple-comparisons test (D–F). (A) Expression of RORγt and T-bet within the γδ T cell compartment of the LN, sLP, and cLP. Numbers indicate percentage of RORγt and T-bet expression. (B) Frequency of RORγt+T-bet+ and RORγt+T-bet− cells within the γδ T cell compartment in LN, sLP, and cLP. (C) Expression of T-bet (histogram) and T-bet mean fluorescence intensity (MFI) (graph) in RORγt+ cLP γδ T cells from WT, STAT5AS710Fhigh (5A), or STAT5BN642H (5B) mice as described in Figure 2. In the graph, colors indicate 2 different experiments. (D–F) Numbers of RORγt+T-bet− (D), RORγt+T-bet+ (E), and RORγt−T-bet+ (F) γδ T cells in the cLP of the indicated hyperactive STAT5A and STAT5B mutant mice or WT control mice. (A and B) n = 10–14 mice, 6 experiments; (C–F) n = 8 WT, 8 STAT5AS710Flow, 8 STAT5AS710Fhigh, 7 STAT5B, and 5 STAT5BN642H mice, 2 experiments.