Constitutively active ezrin desensitizes IL-7 signaling and impairs T cell homeostasis (LYM2P.735)

Abstract

Abstract IL-7 signaling results in tethering of the IL-7 receptor to the actin cytoskeleton, which is mediated by the linker molecules ezrin and moesin. To understand the role of cytoskeleton linker molecules in cytokine signaling, we analyzed mice expressing a constitutively active ezrin transgene in T cells. The ezrin transgene was generated by introducing a point mutation at a conserved C-terminal Thr residue (567T->E) that results in a constitutively open conformation of ezrin. Interestingly, in mice expressing the constitutively active ezrin transgene (T567E-Tg), peripheral T cell numbers were significantly reduced and T cell survival was severely impaired. Moreover, T567E-Tg T cells were defect in IL-7 signaling even as they expressed high levels of surface IL-7 receptor proteins. Additionally, ezrin T567E-Tg induced downregulation of CD8 coreceptor expression, suggesting a “coreceptor tuning” effect of activated ezrin on CD8 T cells. Coreceptor tuning is a model of T cell homeostasis which posits that cytokine signals tailor CD8 coreceptor gene expression to the self-specificity of the TCR. In agreement, TCR disengagement restored IL-7 signaling in T567E-Tg CD8 T cells. Thus, constitutively active ezrin desensitizes IL-7 receptor signaling through increased TCR signaling but not through direct interference with the IL-7 receptor. The molecular mechanisms of ezrin activation on TCR signaling and T cell homeostasis will be discussed.