LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells.
Leukocyte function antigen 1 (LFA-1) is essential for the formation of immune cell synapses and plays a role in the pathophysiology of various autoimmune diseases. We investigated the molecular details of LFA-1 activation during adhesion between cytotoxic cells and a target model leukemia cell. The cytolytic activity of a CD3-CD8+CD56+ natural killer (NK) subset was enhanced when LFA-1 was activated. In a comparison of LFA-1 ligands, intercellular adhesion molecule 2 (ICAM-2) and ICAM-3 promoted LFA-1-directed perforin release, whereas ICAM-1 had little effect. Ligand-induced LFA-1 clustering facilitated perforin release, demonstrating LFA-1 could regulate degranulation mechanisms. LFA-1 induced the activation of src family kinases, Vav1 and p44/42 mitogen-activated protein kinase (MAPK), in human CD56+ NK cells as evidenced by intracellular phospho-epitope measurements that correlated with effector-target cell binding and perforin-granzyme A-mediated cytolytic activity. These results identify novel, specific functional consequence of LFA-1-mediated cytolytic activity in perforin-containing human NK subsets.
Perez
Omar D
OD
Baxter Laboratory for Genetic Pharmacology, Stanford University School of Medicine, Stanford, CA, USA.
Mitchell
Dennis
D
Jager
Gina C
GC
Nolan
Garry P
GP
D019002:CD56 Antigen / Q000032:analysis*; D018414:CD8-Positive T-Lymphocytes; D015550:Cell Degranulation / Q000276:immunology*; D002460:Cell Line; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D008213:Lymphocyte Activation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000502:physiology*; D016131:Lymphocyte Subsets; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins
D019002:CD56 Antigen; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3