An alternative NFAT-activation pathway mediated by IL-7 is critical for early thymocyte development

Nat Immunol. 2013 Feb;14(2):127-35. doi: 10.1038/ni.2507. Epub 2012 Dec 23.

Abstract

Interleukin 7 (IL-7) has a critical role in the development of early CD4(-)CD8(-) double-negative (DN) thymocytes. Although the transcription factor STAT5 is an important component of IL-7 signaling, differences in the phenotypes of mice deficient in STAT5, IL-7, IL-7 receptor alpha (IL-7rα) or the kinase Jak3 suggest the existence of STAT5-independent IL-7 signaling. Here we found that IL-7-Jak3 signals activated the transcription factor NFATc1 in DN thymocytes by phosphorylating Tyr371 in the regulatory region of NFATc1. This NFAT-activation pathway was critical for the survival and development of DN thymocytes, as deficiency in NFATc1 blocked thymocyte development at the DN1 stage, leading to T cell lymphopenia. In addition, our results demonstrated a cooperative function for NFATc1 and STAT5 in guiding thymocyte development in response to IL-7 signals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4 Antigens / genetics
  • CD4 Antigens / immunology
  • CD8 Antigens / genetics
  • CD8 Antigens / immunology
  • Cell Differentiation
  • Gene Expression Regulation
  • Interleukin-7 / genetics*
  • Interleukin-7 / immunology
  • Janus Kinase 3 / genetics
  • Janus Kinase 3 / immunology
  • Lymphopenia / immunology
  • Lymphopenia / pathology
  • Mice
  • Mice, Transgenic
  • NFATC Transcription Factors / deficiency
  • NFATC Transcription Factors / genetics*
  • Phosphorylation
  • Promoter Regions, Genetic
  • Receptors, Interleukin-7 / genetics
  • Receptors, Interleukin-7 / immunology
  • STAT5 Transcription Factor / genetics*
  • STAT5 Transcription Factor / immunology
  • Signal Transduction / immunology*
  • Thymocytes / cytology*
  • Thymocytes / immunology
  • Transcription, Genetic

Substances

  • CD4 Antigens
  • CD8 Antigens
  • Interleukin-7
  • NFATC Transcription Factors
  • Nfatc1 protein, mouse
  • Receptors, Interleukin-7
  • STAT5 Transcription Factor
  • interleukin-7, mouse
  • Jak3 protein, mouse
  • Janus Kinase 3