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 1

STAT5 is necessary for the neonatal expansion of γδT17 cells.

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STAT5 is necessary for the neonatal expansion of γδT17 cells. Flow cytom...
Flow cytometric analysis of γδ T cells in RORγtCRE-STAT5F/F (Cre+) and littermate control mice (Cre−). In graphs, each symbol represents a mouse, and lines represent the median. **P < 0.01, ***P < 0.001, ****P < 0.0001 using Mann-Whitney test. (A) Expression of CD27 and CD44 in order to identify CD27−CD44+ γδT17 cells in the LN. Numbers indicate percentage of CD27−CD44+ within the γδ T cell compartment. (B) Numbers of γδT17 cells in the LN (staining as in A) and skin and frequency of IL-17A–producing cells within the LN γδ T cell compartment. In the skin, γδT17 cells were identified as CD45+CD3loVγ5−TCRβ−TCRγδ+CCR6+. (C) Numbers of CD27+ γδ T cells in the LN and frequency of IFN-γ–producing cells within the LN γδ T cell compartment. (D) Numbers of CD27−CD44+ γδT17 cells in 2- and 7-day-old thymi. (E) Numbers of CD27−CD44+ γδT17 cells in 7- and 14-day-old LN. (F) Frequency of Ki67+RORγt+ or Ki67+CCR6+ cells within the CD44+TCRγδ+ compartment in 7- and 14-day-old LN. (A–C) n = 14–16 mice, 5 experiments; (D) n = 11 (d2) and 9 (d7) Cre− mice and 23 (d2) and 12 (d7) Cre+ mice, 3 experiments; (E) n = 9 (d7) and 4 (d14) Cre− mice and 10 (d7) and 10 (d14) Cre+ mice, 3 experiments; (F) n = 7 (d7) and 6 (d14) Cre− mice and 13 (d7) and 10 (d14) Cre+ mice, 3 experiments.