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A Biochemical Signature for Rapid Recall of Memory CD4 T Cells¹

Division of Transplantation, Department of Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201

Mechanisms for the rapid recall response mediated by memory T cells remain unknown. In this study, we present a novel, multiparameter analysis of TCR-coupled signaling and function in resting and activated naive and memory CD4 T cells, revealing a biochemical basis for immunological recall. We identify a striking elevation in expression of the proximal tyrosine kinase Zap70 in resting Ag-specific and polyclonal mouse memory vs naive CD4 T cells that is stably maintained independent of protein synthesis. Elevated Zap70 protein levels control effector function as IFN- production occurs exclusively from the Zap70^high fraction of activated T cells in vitro and in vivo, and specific down-modulation of Zap70 expression in memory CD4 T cells by small interfering RNA or protein inhibition significantly reduces rapid IFN- production. Downstream of Zap70, we show quantitative differences in distal phosphorylation associated with effector function in naive and memory subsets, with low accumulation of phosphorylation in memory T cells producing IFN- at early time points, contrasting extensive phosphorylation associated with IFN- production following sustained activation of naive T cells. Our results reveal a novel biochemical signature imparted to memory CD4 T cells enabling efficacious responses through increased Zap70 expression and reduced accumulation of downstream signaling events.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health AI42092 awarded to D.L.F.

² Address correspondence and reprint requests to Dr. Donna L. Farber, Department of Surgery, School of Medicine, University of Maryland, Medical School Teaching Facility Building, Room 400, 685 West Baltimore Street, Baltimore, MD 21201. E-mail address: dfarber{at}smail.umaryland.edu

³ Abbreviations used in this paper: siRNA, small interfering RNA; ICS, intracellular cytokine staining; PLC, phospholipase C; CHX, cycloheximide.