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

Nayar, Ribhu
Enos, Megan E.
Prince, Amanda L.
Shin, HyunMu
Hemmers, Saskia
Jiang, Jian-kang
Klein, Ulf
Thomas, Craig J.
Berg, Leslie J.
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Student Authors
Ribhu Nayar; Amanda L. Prince
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UMass Chan Affiliations
Document Type
Journal Article
Publication Date
2012-10-09
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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.

Source

Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):E2794-802. doi: 10.1073/pnas.1205742109. Link to article on publisher's website

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DOI
10.1073/pnas.1205742109
PubMed ID
23011795
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