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Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655
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 β-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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Institutes of Health (AI37584, AI66118) and the Centers for Disease Control and Prevention (CI000101).
2 Address correspondence and reprint requests to Leslie J. Berg, Department of Pathology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, NA 01655. E-mail address: leslie.berg{at}umassmed.edu
3 Abbreviations used in this paper: DP, double positive; 
GAL, -galactosylceramide; 7AAD, 7-aminoactinomycin D; BATF, B cell-activating transcription factor; HSA, heat stable Ag; PKC
, protein kinase C; ROR
t, retinoic acid receptor-related orphan receptor-t; Runx1, runt-related transcription factor 1; SAP, signaling lymphocytic activating molecule-associated protein; SLAM, signaling lymphocytic activating molecule.
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