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 3

RORγtCRE-STAT5F/F mice are resistant to EAE.

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RORγtCRE-STAT5F/F mice are resistant to EAE. Disease progression and flo...
Disease progression and flow cytometric analysis of γδ and CD4+ T cells in RORγtCRE-STAT5F/F (Cre+) and littermate control mice (Cre−) that had been previously immunized with 50 μg MOG peptide in CFA and 200 ng pertussis toxin. In graphs, each symbol represents a mouse, and lines represent the median (except in A). **P < 0.01, ***P < 0.001, ****P < 0.0001 using Mann-Whitney test. (A) Clinical symptoms of EAE until day 21 after immunization. Data are pool of 20 mice per genotype and shown as mean ± SEM. Statistical analysis was performed using 2-way ANOVA with Bonferroni’s multiple-comparisons test. ANOVA P < 0.0001; Bonferroni’s test returned significance for days 11–21 with day 11 P = 0.003 and days 12–21 P < 0.0001. (B and C) Numbers of γδT17 cells in the LN (staining as in Figure 1A) of unimmunized controls (EAE−) and at 11 (B) and 21 (C) days after immunization. (D) Numbers of γδT17 cells in the brain (identified as CD45+CD3+TCRβ−TCRγδ+CD44+CD27−) at days 11 and 21 after immunization. (E) Expression of IL-17A within the LN γδ T cell compartment of unimmunized controls (EAE−) and at 11 and 21 days after immunization. (F) Numbers of CD4+CD44+CD3+TCRβ+ cells in the brain at days 11 and 21 after immunization. (B, C, and E) n = 11–12 mice (d11/21) and 2–8 mice (EAE−), 3 experiments; (D and F) n = 4–6 mice (EAE−), 8 mice (d11), and 11 mice (d21), 3 experiments.