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Efficient T cell activation requires the engagement of a variety of ligand/receptor molecules in addition to T cell receptor (TCR)-major histocompatibility complex (MHC)/peptide interactions. The leukocyte function antigen 1 (LFA-1) and the CD28 glycoprotein have both been implicated 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 the amounts of antigen necessary for T cell activation. In the absence of LFA-1, 100-fold more antigen was required for T cell-antigen-presenting cell (APC) conjugation and all subsequent events of T cell activation, including TCR down-regulation, Ca2+-flux, T cell proliferation, and lytic effector cell induction. Thus, LFA-1 facilitates the functional triggering of TCRs by promoting adhesion of T cells to APCs but does not affect T cell activation otherwise. In contrast, CD28 played an entirely different role during T cell activation. CD28 reduced the number 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 prevented induction of T cell unresponsiveness after stimulation of TCRs. These results demonstrate that LFA-1 and CD28 exhibit distinct, nonoverlapping ways to influence T cell activation and suggest that the terms costimulation and signal 2 should be revisited.

Type

Journal article

Journal

Immunity

Publication Date

10/1997

Volume

7

Pages

549 - 557

Keywords

Animals, Antigen-Presenting Cells, Antigens, Viral, CD28 Antigens, Calcium, Cell Adhesion, Cell Adhesion Molecules, Clonal Anergy, Down-Regulation, Interleukin-2, Lymphocyte Activation, Lymphocyte Function-Associated Antigen-1, Lymphocytic choriomeningitis virus, Mice, Mice, Transgenic, Peptides, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes