Tec Kinases Itk and Rlk Are Required for CD8+ T Cell Responses to Virus Infection Independent of Their Role in CD4+ T Cell Help

Abstract

Itk and Rlk are members of the Tec kinase family of nonreceptor protein tyrosine kinases that are expressed in T cells, NK cells, and mast cells. These proteins are involved in the regulation of signaling processes downstream of the TCR in CD4+ T cells, particularly in the phosphorylation of phospholipase C-γ1 after TCR activation; furthermore, both Itk and Rlk are important in CD4+ T cell development, differentiation, function, and homeostasis. However, few studies have addressed the roles of these kinases in CD8+ T cell signaling and function. Using Itk−/− and Itk−/−Rlk−/− mice, we examined the roles of these Tec family kinases in CD8+ T cells, both in vitro and in vivo. These studies demonstrate that the loss of Itk and Rlk impairs TCR-dependent signaling, causing defects in phospholipase C-γ1, p38, and ERK activation as well as defects in calcium flux and cytokine production in vitro and expansion and effector cytokine production by CD8+ T cells in response to viral infection. These defects cannot be rescued by providing virus-specific CD4+ T cell help, thereby substantiating the important role of Tec kinases in CD8+ T cell signaling.