Costimulation by extracellular matrix proteins determines the response to TCR ligation

Although ligation of the T-cell antigen receptor (TCR) is central to the re sponsiveness and antigen specificity of T-cells, it is insufficient to elic it a response. To determine whether the need for costimulation reflects ina dequate strength of signal transduction through the TCR or an absolute bloc k of signaling in the absence of a coligand, we studied T-cell activation u nder serum-free conditions eliminating costimulation by various extracellul ar matrix proteins which otherwise have an omnipresent and frequently overl ooked effect. Engagement of the TCR leads to induction of Fas, but not to m easurable IL-2 secretion or apoptosis. Those activation parameters are indu ced by costimulation through integrin alpha (v)beta (3). Furthermore, T-cel l survival or elimination is determined by the type of ligand binding to th is coreceptor with vitronectin, fibronectin, and fibrinogen efficiently ind ucing apoptosis and IL-2 production while osteopontin and entactin mediate IL-2 secretion comparably without causing programmed cell death. Consistent with the cytokine properties of these ligands, differential costimulation depends on their presentation in soluble rather than immobilized form. The determination of elimination versus survival of activated T-cells by coliga tion of beta (3)-integrins may have bearing on the fundamental postthymic m echanisms that shape the T-cell repertoire. (C) 2001 Academic Press.