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.
This work was supported by intramural funds from the National Human Genome Research Institute (P.L.S. and S.M.K.) and by Wellcome Trust Grants  and  (J.C.S. and G.M.G.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- CellTrace Violet
- endoplasmic reticulum
- inducible T cell kinase
- lysosomal-associated membrane protein 1
- lactate dehydrogenase
- National Institutes of Health
- signaling lymphocyte activation molecule–associated protein
- transmission electron microscopy
- wild type
- X-linked lymphoproliferative syndrome.
- Received July 11, 2016.
- Accepted January 19, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.