Activation of naïve CD4+ T cells re-tunes STAT1 signaling to deliver unique cytokine responses in memory CD4+ T cells

Nat Immunol. 2019 Apr;20(4):458-470. doi: 10.1038/s41590-019-0350-0. Epub 2019 Mar 19.

Abstract

The cytokine IL-6 controls the survival, proliferation and effector characteristics of lymphocytes through activation of the transcription factors STAT1 and STAT3. While STAT3 activity is an ever-present feature of IL-6 signaling in CD4+ T cells, prior activation via the T cell antigen receptor limits IL-6's control of STAT1 in effector and memory populations. Here we found that phosphorylation of STAT1 in response to IL-6 was regulated by the tyrosine phosphatases PTPN2 and PTPN22 expressed in response to the activation of naïve CD4+ T cells. Transcriptomics and chromatin immunoprecipitation-sequencing (ChIP-seq) of IL-6 responses in naïve and effector memory CD4+ T cells showed how the suppression of STAT1 activation shaped the functional identity and effector characteristics of memory CD4+ T cells. Thus, tyrosine phosphatases induced by the activation of naïve T cells determine the way activated or memory CD4+ T cells sense and interpret cytokine signals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / enzymology
  • Arthritis, Rheumatoid / pathology
  • CD4-Positive T-Lymphocytes / enzymology
  • CD4-Positive T-Lymphocytes / immunology*
  • CHO Cells
  • Cells, Cultured
  • Cricetulus
  • Gene Expression Regulation
  • Humans
  • Immunologic Memory
  • Interleukin-6 / physiology
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Promoter Regions, Genetic
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / metabolism
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Interleukin-6 / physiology
  • STAT1 Transcription Factor / metabolism*
  • Signal Transduction*
  • Synovial Membrane / immunology
  • Transcription, Genetic

Substances

  • Interleukin-6
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin-6
  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • PTPN2 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Ptpn2 protein, mouse