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 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.
Bachmann
M F
MF
Ontario Cancer Institute, Department of Medical Biophysics, Toronto, Canada.
McKall-Faienza
K
K
Schmits
R
R
Bouchard
D
D
Beach
J
J
Speiser
D E
DE
Mak
T W
TW
Ohashi
P S
PS
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D018106:CD28 Antigens / Q000502:physiology*; D002118:Calcium / Q000502:physiology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000502:physiology; D017635:Clonal Anergy; D015536:Down-Regulation; D007376:Interleukin-2 / Q000502:physiology; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
D000956:Antigens, Viral; D018106:CD28 Antigens; D015815:Cell Adhesion Molecules; D007376:Interleukin-2; D016169:Lymphocyte Function-Associated Antigen-1; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D002118:Calcium