Semmrich Monika, Smith Andrew, Feterowski Carolin, Beer Sandra, Engelhardt Britta, Busch Dirk H, Bartsch Bernadett, Laschinger Melanie, Hogg Nancy, Pfeffer Klaus, Holzmann Bernhard
Department of Surgery, Immunology, and Hygiene, Technische Universität München, 81675 Munich, Germany.
J Exp Med. 2005 Jun 20;201(12):1987-98. doi: 10.1084/jem.20041850. Epub 2005 Jun 13.
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.
配体结合的动态调节被认为对整合素功能至关重要。然而，体内整合素功能的活性调节的重要性在很大程度上尚不清楚。在此，我们应用基因靶向技术在小鼠种系中删除淋巴细胞功能相关抗原-1（LFA-1）α（L）亚基胞质结构域的GFFKR序列。来自Lfa-1（d/d）突变小鼠的淋巴细胞表现出LFA-1介导的细胞黏附的组成性激活，以及从细胞间黏附分子-1的去黏附受损，导致细胞迁移缺陷。相比之下，Lfa-1（d/d）细胞中通过LFA-1的信号传导不受影响。Lfa-1（d/d）小鼠中，超抗原负载和同种异体抗原呈递细胞（APC）诱导的T细胞活化、细胞毒性T细胞活性、T细胞依赖性体液免疫反应以及无菌性腹膜炎期间的中性粒细胞募集均受损。因此，LFA-1的失活和LFA-1介导的细胞接触的解体似乎对正常免疫反应的产生至关重要。
