TC-PTP regulates the IL-7 transcriptional response during murine early T cell development

Sci Rep. 2017 Oct 16;7(1):13275. doi: 10.1038/s41598-017-13673-w.

Abstract

Cytokines play a critical role in directing the discrete and gradual transcriptional changes that define T cell development. The interleukin-7 receptor (IL-7R), via its activation of the JAK-STAT pathway, promotes gene programs that change dynamically as cells progress through T cell differentiation. The molecular mechanism(s) directing differential gene expression downstream of the IL-7R are not fully elucidated. Here, we have identified T cell protein tyrosine phosphatase (TC-PTP), also known as PTPN2, as a negative regulator of IL-7R-STAT signaling in T cell progenitors, contributing to both the quantitative and qualitative nature of STAT-gene targeting. Novel genetic strategies used to modulate TC-PTP expression demonstrate that depletion of TC-PTP expression heightens the phosphorylation of STAT family members, causing aberrant expression of an interferon-response gene profile. Such molecular re-programming results in deregulation of early development checkpoints culminating in inefficient differentiation of CD4+CD8+ double positive cells. TC-PTP is therefore shown to be required to safeguard the dynamic transcriptome necessary for efficient T cell differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Cell Differentiation / genetics*
  • Gene Expression Regulation / drug effects
  • Inflammation Mediators
  • Interferons / pharmacology
  • Interleukin-7 / genetics*
  • Interleukin-7 / metabolism
  • Lymphopoiesis / genetics
  • Mice
  • Mice, Knockout
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / metabolism*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / metabolism*
  • Transcription, Genetic*

Substances

  • Biomarkers
  • Inflammation Mediators
  • Interleukin-7
  • RNA, Small Interfering
  • Interferons
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Ptpn2 protein, mouse

Grants and funding