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and IL-4 Production by NKT Cells1Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, University of Rochester, Rochester, NY 14642
NKT cells rapidly secrete cytokines upon TCR stimulation and thus may modulate the acquired immune response. Recent studies suggest that signaling for development and effector function in NKT cells may differ from conventional T cells. The tyrosine kinase Itk is activated downstream of the TCR, and its absence in CD4+ T cells results in impaired Th2, but not Th1 responses. In this study, we investigated NKT cell function in the absence of Itk as impaired type 2 responses in vivo could be manifest through IL-4 defects in a number of cell types. We show that Itk-deficient NKT cells up-regulate IL-4 mRNA in the thymus and express constitutive IL-4 and IFN-
transcripts in peripheral organs. Thus, Itk is not required for the developmental activation of cytokine loci in NKT cells. Nevertheless, Itk-deficient NKT cells are severely impaired in IL-4 protein production. Strikingly, unlike conventional CD4+ T cells, Itk-deficient NKT cells also have profound defects in IFN- production. Furthermore, both IL-4 and IFN- production were markedly impaired following in vivo challenge with 
-galactosyl ceramide. Function can be restored in Itk-deficient NKT cells by provision of calcium signals using ionomycin. These results suggest that NKT cells are highly dependent on Itk for IL-4- and IFN--mediated effector function. Thus, the pattern of cytokine genes that are affected by Itk deficiency appears to be cell lineage-specific, likely reflecting differences in activation threshold between immune effectors. The severe defect in NKT cell function may underlie a number of the Th1 and Th2 immune defects in Itk-deficient mice.
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 National Institutes of Health Grant AI50201 (to D.J.F.), the Howard Hughes Medical Institute Biomedical Research Program for Medical Schools (to D.J.F.), and Training Grant T32-DE07165 (to B.A.).
2 Address correspondence and reprint requests to Dr. Deborah J. Fowell, Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, University of Rochester, 601 Elmwood Ave, Box 609, Rochester, NY 14642. E-mail address: deborah_fowell{at}urmc.rochester.edu
3 Abbreviations used in this paper: Galcer, -galactosyl ceramide; PLC, phospholipase C; SAP, signaling lymphocytic activation molecule-associated protein; PKC
, protein kinase C; WT, wild type; eGFP, enhanced GFP.
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  J. Hu and A. August Naive and Innate Memory Phenotype CD4+ T Cells Have Different Requirements for Active Itk for Their Development J. Immunol., May 15, 2008; 180(10): 6544 - 6552. [Abstract] [Full Text] [PDF]
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M. Felices and L. J. Berg The Tec Kinases Itk and Rlk Regulate NKT Cell Maturation, Cytokine Production, and Survival J. Immunol., March 1, 2008; 180(5): 3007 - 3018. [Abstract] [Full Text] [PDF]
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