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

J Clin Invest. 2020 May 1;130(5):2496-2508. doi: 10.1172/JCI131241.


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.

Keywords: Cellular immune response; Immunology; T cell development; T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cellular Microenvironment / genetics
  • Cellular Microenvironment / immunology*
  • Cytokines / genetics
  • Cytokines / immunology
  • Immunity, Innate*
  • Intestines / cytology
  • Intestines / immunology*
  • Mice
  • Mice, Transgenic
  • Organ Specificity / genetics
  • Organ Specificity / immunology
  • Receptors, Antigen, T-Cell, gamma-delta / genetics
  • Receptors, Antigen, T-Cell, gamma-delta / immunology*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / immunology*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*


  • Cytokines
  • Receptors, Antigen, T-Cell, gamma-delta
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Stat3 protein, mouse
  • Stat5a protein, mouse
  • Stat5b protein, mouse