TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation

Ribhu Nayar, Megan Enos, Amanda Prince, Hyun Mu Shin, Saskia Hemmers, Jian Kang Jiang, Ulf Klein, Craig J. Thomas, Leslie J. Berg

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

CD8+ T-cell development in the thymus generates a predominant population of conventional naive cells, along with minor populations of "innate" T cells that resemble memory cells. Recent studies analyzing a variety of KO or knock-in mice have indicated that impairments in the T-cell receptor (TCR) signaling pathway produce increased numbers of innate CD8 + T cells, characterized by their high expression of CD44, CD122, CXCR3, and the transcription factor, Eomesodermin (Eomes). One component of this altered development is a non-CD8+ T cell-intrinsic role for IL-4. To determine whether reduced TCR signaling within the CD8+ T cells might also contribute to this pathway, we investigated the role of the transcription factor, IFN regulatory factor 4 (IRF4). IRF4 is up-regulated following TCR stimulation in WT T cells; further, this up-regulation is impaired in T cells treated with a small-molecule inhibitor of the Tec family tyrosine kinase, IL-2 inducible T-cell kinase (ITK). In contrast to WT cells, activation of IRF4-deficient CD8+ T cells leads to rapid and robust expression of Eomes, which is further enhanced by IL-4 stimulation. In addition, inhibition of ITK together with IL-4 increases Eomeso up-regulation. These data indicate that ITK signaling promotes IRF4 up-regulation following CD8+ T-cell activation and that this signaling pathway normally suppresses Eomes expression, thereby regulating the differentiation pathway of CD8+ T cells.

Original languageEnglish
Pages (from-to)E2794-E2802
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number41
DOIs
StatePublished - 9 Oct 2012
Externally publishedYes

Keywords

  • ITK inhibitor
  • T-cell receptor signal strength
  • T-cell signaling

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