T cell receptor antagonism interferes with MHC clustering and integrin patterning during immunological synapse formation.
T cell activation by nonself peptide-major histocompatibility complex (MHC) antigenic complexes can be blocked by particular sequence variants in a process termed T cell receptor antagonism. The inhibition mechanism is not understood, although such variants are encountered in viral infections and may aid immune evasion. Here, we study the effect of antagonist peptides on immunological synapse formation by T cells. This cellular communication process features early integrin engagement and T cell motility arrest, referred to as the "stop signal." We find that synapses formed on membranes presenting antagonist-agonist complexes display reduced MHC density, which leads to reduced T cell proliferation that is not overcome by the costimulatory ligands CD48 and B7-1. Most T cells fail to arrest and crawl slowly with a dense ICAM-1 crescent at the leading edge. Similar aberrant patterns of LFA-1/ICAM-1 engagement in live T-B couples correlate with reduced calcium flux and IL-2 secretion. Hence, antagonist peptides selectively disable MHC clustering and the stop signal, whereas LFA-1 valency up-regulation occurs normally.
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.
Cenk
C
Sumen
Michael L
ML
Dustin
Mark M
MM
Davis
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000378:metabolism; D000071178:CD48 Antigen; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D007091:Image Processing, Computer-Assisted; D016023:Integrins / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007700:Kinetics; D008051:Lipid Bilayers / Q000737:chemistry; D008211:Lymphocyte Cooperation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008285:Major Histocompatibility Complex; D051379:Mice; D008822:Mice, Transgenic; D018715:Microscopy, Video; D018448:Models, Immunological; D010455:Peptides / Q000737:chemistry; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D013569:Synapses / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism; D015854:Up-Regulation
D015703:Antigens, CD; D018122:B7-1 Antigen; D000071178:CD48 Antigen; C000604066:Cd48 protein, mouse; D016023:Integrins; D008051:Lipid Bilayers; D016169:Lymphocyte Function-Associated Antigen-1; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1