DISTINCT ROLES FOR LFA-1 AND CD28 DURING ACTIVATION OF NAIVE T-CELLS - ADHESION VERSUS COSTIMULATION

Efficient T cell activation requires the engagement of a variety of li gand/receptor molecules in addition to T cell receptor (TCR)-major his tocompatibility complex (MHC)/peptide interactions. The leukocyte func tion antigen 1 (LFA-1) and the CD28 glycoprotein have both been implic ated in T cell activation. The present study dissects the roles of LFA -1 and CD28 in the activation of naive virus-specific CD8(+) T cells. We demonstrate that LFA-1 facilitates T cell activation by lowering th e amounts of antigen necessary for T cell activation. In the absence o f LFA-1, 100-fold more antigen was required for T cell-antigen-present ing cell (APC) conjugation and all subsequent events of T cell activat ion, including TCR down-regulation, Ca2+-flux, T cell proliferation, a nd lytic effector cell induction. Thus, LFA-1 facilitates the function al triggering of TCRs by promoting adhesion of T cells to APCs but doe s not affect T cell activation otherwise. In contrast, CD28 played an entirely different role during T cell activation. CD28 reduced the num ber of TCRs that had to be triggered for T cell activation and allowed activation of T cells by low affinity ligands. CD28 but not LFA-1 pre vented induction of T cell unresponsiveness after stimulation of TCRs. These results demonstrate that LFA-1 and CD28 exhibit distinct, nonov erlapping ways to influence T cell activation and suggest that the ter ms costimulation and signal 2 should be revisited.