The Tec kinases Itk and Rlk regulate NKT cell maturation, cytokine production, and survival.
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.
Felices
Martin
M
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Berg
Leslie J
LJ
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005810:Multigene Family / Q000235:genetics / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase