A biochemical signature for rapid recall of memory CD4 T cells (87.41)

Abstract

Abstract Mechanisms for the rapid effector responses mediated by memory T cells remain unknown. In this study, we used multiparameter analysis of intracellular signaling and function in naive and memory T cells in vitro and in vivo to determine a biochemical basis for immunological recall. We identify here a striking and specific elevation in expression of the ZAP-70 protein tyrosine kinase in resting memory compared to naive CD4 T cells that is stably maintained independent of protein synthesis, whereas low ZAP-70 expression in naive cells increases with sustained antigenic stimulation requiring new protein synthesis. We demonstrate that ZAP-70 levels control effector function, as specific downregulation of ZAP-70 expression in memory CD4 T cells abrogates rapid effector function, and acquisition of effector function occurs exclusively from activated T cells that have upregulated ZAP-70. Moreover, rapid IFN-γ production from ZAP-70hi memory CD4 T cells occurs via a quantitative bypass in distal signaling in vitro and in vivo, contrasting the increased distal phosphorylation events that precede late IFN-γ production from activated naive CD4 T cells. Our findings reveal a novel biochemical signature imparted to memory CD4 T cells enabling efficient functional coupling through increased ZAP-70 expression and reduced downstream signaling events. This work was supported by NIH AI42092