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

Paradigms and Technologies

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.

Authors

Nayar, Ribhu; Enos, Megan; Prince, Amanda; Shin, Hyunmu; Hemmers, Saskia; Jiang, Jian-Kang; Klein, Ulf; Thomas, Craig; Berg, Leslie J;

Keywords

  • Animals
  • CD4-Positive T-Lymphocytes/ immunology
  • CD4-Positive T-Lymphocytes/ metabolism
  • CD8-Positive T-Lymphocytes/ immunology
  • CD8-Positive T-Lymphocytes/ metabolism
  • Cell Differentiation/ genetics
  • Cell Differentiation/ immunology
  • Cells, Cultured
  • Female
  • Flow Cytometry
  • Forkhead Transcription Factors/ genetics
  • Forkhead Transcription Factors/ immunology
  • Forkhead Transcription Factors/ metabolism
  • Gene Expression/ drug effects
  • Interferon Regulatory Factors/ genetics
  • Interferon Regulatory Factors/ immunology
  • Interferon Regulatory Factors/ metabolism
  • Interleukin-4/ pharmacology
  • Lymphocyte Activation/ immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Protein-Tyrosine Kinases/ genetics
  • Protein-Tyrosine Kinases/ immunology
  • Protein-Tyrosine Kinases/ metabolism
  • Receptors, Antigen, T-Cell, alpha-beta/ genetics
  • Receptors, Antigen, T-Cell, alpha-beta/ immunology
  • Receptors, Antigen, T-Cell, alpha-beta/ metabolism
  • Signal Transduction/ genetics
  • Signal Transduction/ immunology
  • T-Box Domain Proteins/ genetics
  • T-Box Domain Proteins/ immunology
  • T-Box Domain Proteins/ metabolism
  • T-Lymphocytes, Regulatory/ immunology
  • T-Lymphocytes, Regulatory/ metabolism
  • Thymocytes/ immunology
  • Thymocytes/ metabolism
  • Thymus Gland/ cytology
  • Thymus Gland/ immunology
  • Thymus Gland/ metabolism

External Links