Importance of integrin LFA-1 deactivation for the generation of immune responses.
The dynamic regulation of ligand binding is considered crucial for integrin function. However, the importance of activity regulation for integrin function in vivo is largely unknown. Here, we have applied gene targeting to delete the GFFKR sequence of the lymphocyte function-associated antigen-1 (LFA-1) alpha(L) subunit cytoplasmic domain in mouse germline. Lymphocytes from Lfa-1(d/d) mutant mice showed constitutive activation of LFA-1-mediated cell adhesion and impaired de-adhesion from intercellular adhesion molecule-1 that resulted in defective cell migration. In contrast, signaling through LFA-1 was not affected in Lfa-1(d/d) cells. T cell activation by superantigen-loaded and allogeneic APCs, cytotoxic T cell activity, T-dependent humoral immune responses, and neutrophil recruitment during aseptic peritonitis were impaired in Lfa-1(d/d) mice. Thus, deactivation of LFA-1 and disassembly of LFA-1-mediated cell contacts seem to be vital for the generation of normal immune responses.
Semmrich
Monika
M
Department of Surgery, Immunology, and Hygiene, Technische Universität München, 81675 Munich, Germany.
Smith
Andrew
A
Feterowski
Carolin
C
Beer
Sandra
S
Engelhardt
Britta
B
Busch
Dirk H
DH
Bartsch
Bernadett
B
Laschinger
Melanie
M
Hogg
Nancy
N
Pfeffer
Klaus
K
Holzmann
Bernhard
B
D000818:Animals; D000906:Antibodies / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology*; D022202:Chromosomes, Artificial, Bacterial; D017931:DNA Primers; D018390:Gene Targeting; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008208:Lymphatic System / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018715:Microscopy, Video; D009154:Mutation / Q000235:genetics; D038081:Organogenesis / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D017931:DNA Primers; D016169:Lymphocyte Function-Associated Antigen-1; D021122:Protein Subunits; D018799:Intercellular Adhesion Molecule-1