A fundamental subdivision of circulating lymphocytes defined by adhesion to mucosal addressin cell adhesion molecule-1. Comparison with vascular cell adhesion molecule-1 and correlation with beta 7 integrins and memory differentiation.
The leukocyte integrin alpha 4 beta 7 is a receptor for the vascular mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Most circulating B and T lymphocytes in man are alpha 4+, and on these cells the regulated display of the beta 7 integrin chain determines the expression of alpha 4 beta 7 and, in large part, binding to MAdCAM-1. Among CD4+ T cells, beta 7 high memory cells (including the L-selectin+ subset) bind MAdCAM-1 better than beta 7int naive cells; whereas beta 7- memory cells,including skin homing lymphocytes, interact poorly if at all. Circulating alpha E beta 7+ T cells are alpha 4 beta 7high and also bind MAdCAM-1 well. B cells are also subdivided by beta 7 expression, and beta 7+ B cells bind MAdCAM-1 better than the beta 7low/- subset. The related vascular ligand vascular cell adhesion molecule-1 (VCAM-1), expressed on endothelium primarily in nonmucosal sites of inflammation, interacts with blood lymphocytes (including beta 7high T cells) almost exclusively via alpha 4 beta 1 and binds beta 7low/-(beta 1high) better than beta 7+ B cells and memory cells better than naive CD4+ cells. beta 7-(beta 1high) memory T cells are somewhat enriched over beta 7high memory cells at low (but not at high) VCAM-1 densities. Interestingly, CD56+ NK cells, which express both alpha 4 beta 7 and alpha 4 beta 1, bind well to VCAM-1 but poorly to MAdCAM-1. The findings indicate that the display and function of alpha 4 beta 7 determine integrin-dependent blood lymphocyte interactions with MAdCAM-1, thus delineating discrete mucosal vs nonmucosal lymphocyte populations in vivo; that alpha 4 beta 1 dominates blood lymphocyte interactions with VCAM-1; and that quantitative and qualitative regulation of MAdCAM-1 vs VCAM-1 can critically control the recruitment of specialized lymphocyte subsets during inflammation.
Rott
L S
LS
Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University, CA 94305.
Briskin
M J
MJ
Andrew
D P
DP
Berg
E L
EL
Butcher
E C
EC
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules; D002454:Cell Differentiation / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis / Q000097:blood*; D007156:Immunologic Memory / Q000187:drug effects; D039641:Integrin beta Chains; D016023:Integrins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008345:Manganese / Q000494:pharmacology; D009088:Mucoproteins / Q000096:biosynthesis / Q000097:blood*; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D014162:Transfection / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood* / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D039641:Integrin beta Chains; D016023:Integrins; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D019010:Vascular Cell Adhesion Molecule-1; C071777:integrin alpha4beta7; C070709:integrin alphaEbeta7; C091368:integrin beta7; D008345:Manganese