title: Inducible T Cell Kinase Regulates the Acquisition of Cytolytic Capacity and Degranulation in CD8+CTLs.
abstract: Patients with mutations in inducible T cell kinase (ITK) are susceptible to viral infections, particularly EBV, suggesting that these patients have defective function of CD8+CTLs. In this study, we evaluated the effects of ITK deficiency on cytolysis in murine CTLs deficient in ITK, and both human and murine cells treated with an ITK inhibitor. We find that ITK deficiency leads to a global defect in the cytolysis of multiple targets. The absence of ITK both affected CTL expansion and delayed the expression of cytolytic effectors during activation. Furthermore, absence of ITK led to a previously unappreciated intrinsic defect in degranulation. Nonetheless, these defects could be overcome by early or prolonged exposure to IL-2, or by addition of IL-12 to cultures, revealing that cytokine signaling could restore the acquisition of effector function in ITK-deficient CD8+T cells. Our results provide new insight into the effect of ITK and suboptimal TCR signaling on CD8+T cell function, and how these may contribute to phenotypes associated with ITK deficiency.
authors.affiliation: National Human Genome Research Institute, Bethesda, MD 20892; and.
authors.forename: Senta M
authors.initials: SM
authors.lastname: Kapnick
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
authors.forename: Jane C
authors.identifier: 0000-0003-1459-9299
authors.initials: JC
authors.lastname: Stinchcombe
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
authors.forename: Gillian M
authors.identifier: 0000-0003-0434-5842
authors.initials: GM
authors.lastname: Griffiths
authors.affiliation: National Human Genome Research Institute, Bethesda, MD 20892; and pams@nhgri.nih.gov.
authors.forename: Pamela L
authors.identifier: 0000-0001-6318-9187
authors.initials: PL
authors.lastname: Schwartzberg
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015550:Cell Degranulation / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D011505:Protein-Tyrosine Kinases / Q000276:immunology*
chemical_list: D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase