T cells that interact with antigen-specific APCs an mount a wide spectrum of responses that range rom induction of cytokine production and proliferaion to induction of anergy, as defined by lack of roliferation and IL-2 secretion [1-3], and even to riggering programmed cell death [4-8]. The detailed egulatory mechanisms that link receptor proximal ctivation events at the T cell membrane to such ifferential outcomes are not known. The study of uch regulatory mechanisms is complicated by the fact hat cellular responses are determined by the engageent of multiple activating and inhibitory receptors n the T cell and the APC. These receptors engage an ven larger number of cytoplasmic proteins that feed nto many sequential, parallel, and intersecting biohemical pathways. Engagement of the TCR activates the Src-related yrosine kinases Lck and Fyn by as yet unknown echanisms [9-11]. These kinases rapidly phosphorlate several specific substrates, including the immuoreceptor tyrosine activation motifs of the TCRssociated chains. Binding of phosphorylated mmunoreceptor tyrosine activation motifs to the cyosolic tyrosine kinase ZAP-70 and its phosphorylaion by Lck result in activation of this enzyme [11]. AP-70 is a pivotal relay: by phosphorylating the caffold protein LAT, it creates sites for recruitment f additional adaptor and signaling proteins [11,12]. hese initiating signals are further relayed through ytosolic kinases, including phospho-lipate C and hosphatidylinositol-3 kinase [13-20]. TCR-activated hospho-lipate C hydrolyzes the phospholipid phoshatidylinositol 4, 5 biphosphonate to generate the econd messengers inositol 1, 4, 5-triphosphate and iacylglycerol [21,22]. These second messengers genrate increases in free intracellular calcium, activation f serine-threonine kinases, including alpha serine/ hreonine kinase, pyruvate dehydrogenase kinase-1, nd protein kinase C (PKC), which together culmiate in coordinated changes in gene expression. The xact branching points along these pathways that can ead to differential outcomes are not yet fully defined. c ole of PKCin T Cell Activation