The Tec kinases Itk and Rlk regulate NKT cell maturation, cytokine production, and survival
Graduate School of Biomedical Sciences; Department of Pathology
Medical Subject Headings
Animals; Cell Differentiation; Cell Survival; Cytokines; Gene Expression Regulation, Enzymologic; Immunophenotyping; Killer Cells, Natural; Mice; Mice, Inbred C57BL; Mice, Knockout; Multigene Family; Protein-Tyrosine Kinases; Signal Transduction; T-Lymphocyte Subsets
Life Sciences | Medicine and Health Sciences
The Tec kinases Itk and Rlk are required for efficient positive selection of conventional CD4+ and CD8+ T cells in the thymus. In contrast, recent studies have shown that these Tec kinases are dispensable for the development of CD8+ T cells with characteristics of innate T cells. These findings raise questions about the potential role of Itk and Rlk in NKT cell development, because NKT cells represent a subset of innate T cells. To address this issue, we examined invariant NKT cells in Itk-/- and Itk/Rlk-/- mice. We find, as has been reported previously, that Itk-/- mice have reduced numbers of NKT cells with a predominantly immature phenotype. We further show that this defect is greatly exacerbated in the absence of both Itk and Rlk, leading to a 7-fold reduction in invariant NKT cell numbers in the thymus of Itk/Rlk-/- mice and a more severe block in NKT cell maturation. Splenic Itk-/- and Itk/Rlk-/- NKT cells are also functionally defective, because they produce little to no cytokine following in vivo activation. Tec kinase-deficient NKT cells also show enhanced cell death in the spleen. These defects correlate with greatly diminished expression of CD122, the IL-2R/IL-15R beta-chain, and impaired expression of the T-box transcription factor, T-bet. These data indicate that the Tec kinases Itk and Rlk provide important signals for terminal maturation, efficient cytokine production, and peripheral survival of NKT cells.
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Citation: J Immunol. 2008 Mar 1;180(5):3007-18.