Low-affinity LFA-1/ICAM-3 interactions augment LFA-1/ICAM-1-mediated T cell adhesion and signaling by redistribution of LFA-1.
Although ICAM-3 is implicated in both adhesion and signal transduction events of leukocytes, its low affinity for LFA-1 compared to other ligands of LFA-1 has puzzled many investigators. Here we investigated the role of ICAM-3 in supporting LFA-1-mediated ICAM-1 binding and subsequently cell signaling. We observed that although ICAM-3 binds poorly to LFA-1 expressed on resting T cells, it specifically facilitates and increases LFA-1-mediated adhesion to the high affinity ligand of LFA-1, ICAM-1. We demonstrate that low-affinity binding of LFA-1 to ICAM-3 together with ICAM-1 alters the cell surface distribution of LFA-1 dramatically, inducing large clusters of LFA-1 that facilitate ICAM-1 binding after LFA-1 activation. We found that LFA-1-mediated ICAM-1 cell-cell interactions such as T cell proliferation greatly depend on low affinity LFA-1/ICAM-3 interactions that enhance stable LFA-1/ICAM-1 cell-cell contact. Taken together, these data demonstrate that low affinity LFA-1 binding to ICAM-3 regulates strong LFA-1/ICAM-1-mediated adhesion by driving LFA-1 into clusters to facilitate cell-cell interactions that take place in the immune system.
Bleijs
D A
DA
Department of Tumor Immunology, University of Nijmegen, Nijmegen, the Netherlands.
Binnerts
M E
ME
van Vliet
S J
SJ
Figdor
C G
CG
van Kooyk
Y
Y
D015703:Antigens, CD; D000943:Antigens, Differentiation; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000494:pharmacology / Q000502:physiology*; D002455:Cell Division; D002478:Cells, Cultured; D006801:Humans; D020014:K562 Cells; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D009363:Neoplasm Proteins / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015815:Cell Adhesion Molecules; C483616:ICAM3 protein, human; D016169:Lymphocyte Function-Associated Antigen-1; D009363:Neoplasm Proteins; D011994:Recombinant Proteins