TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation
Immunology & Microbiology
Department of Pathology
Medical Subject Headings
Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Differentiation; Cells, Cultured; Female; Flow Cytometry; Forkhead Transcription Factors; Gene Expression; Interferon Regulatory Factors; Interleukin-4; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Protein-Tyrosine Kinases; Receptors, Antigen, T-Cell, alpha-beta; Signal Transduction; T-Box Domain Proteins; T-Lymphocytes, Regulatory; Thymocytes; Thymus Gland
Cellular and Molecular Physiology | Immunology and Infectious Disease
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.
Proceedings of the National Academy of Sciences of the United States of America
Nayar, Ribhu; Enos, Megan E.; Prince, Amanda L.; Shin, HyunMu; Hemmers, Saskia; Jiang, Jian-kang; Klein, Ulf; Thomas, Craig J.; and Berg, Leslie J., "TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation" (2012). GSBS Student Publications. 1830.