Inducible T cell kinase regulates CD8+ T lymphocyte effector function

Tuesday, September 23, 2014 — Poster Session III
12:00 p.m. – 2:00 p.m.	FAES Academic Center	NHGRI	IMMUNO-6

* FARE Award Winner

Authors

• S.M. Kapnick
• P.L. Schwartzberg

Abstract

CD8+ cytotoxic T-lymphocytes (CTLs) are critical for eliminating virally infected cells, and defects in CTL responses are implicated in lymphoproliferative diseases. Patients with mutations in inducible T-cell kinase (Itk), a tyrosine kinase that serves as an amplifier of T-cell receptor (TCR) signaling, develop lymphoproliferative disease associated with ineffective responses against EBV, a virus that infects B-cells. This phenotype is similar to X-linked lymphoproliferative syndrome, where mutations in the adaptor SAP lead to fatal EBV infections associated with specific defects in B-cell cytolysis. Unlike SAP-deficient CTLs however, we found CTLs from Itk-deficient mice exhibit impaired killing of multiple targets, suggesting Itk-deficiency leads to global defects in cytolysis. Killing by CTLs begins when TCR signaling triggers adherence to targets, centrosome polarization, and release of secretory granules inducing cytolysis of targets. Although early events such as adhesion, actin ring formation, and polarization of lytic machinery were intact in Itk-deficient murine CTLs, we found defects in granule secretion suggesting Itk may play an unappreciated role in the final stages of killing. Exploration of the role of Itk in CTL function will provide clues as to how early TCR signaling contributes to cytolysis, and why mutations in Itk lead to lymphoproliferative diseases.

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