Importance of integrin LFA-1 deactivation for the generation of immune responses

Author:

Semmrich Monika1,Smith Andrew2,Feterowski Carolin1,Beer Sandra13,Engelhardt Britta4,Busch Dirk H.5,Bartsch Bernadett1,Laschinger Melanie2,Hogg Nancy2,Pfeffer Klaus3,Holzmann Bernhard1

Affiliation:

1. Department of Surgery, Immunology, and Hygiene, Technische Universität München, 81675 Munich, Germany

2. Cancer Research UK, London Research Institute, London WC2A 3PX, England, UK

3. Institute of Medical Microbiology, Universität Düsseldorf, 40225 Düsseldorf, Germany

4. Theodor Kocher Institute, University of Bern, CH-3012 Bern, Switzerland

5. Institute of Medical Microbiology, Immunology, and Hygiene, Technische Universität München, 81675 Munich, Germany

Abstract

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) αL subunit cytoplasmic domain in mouse germline. Lymphocytes from Lfa-1d/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-1d/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-1d/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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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