The beta1 and beta3 integrins promote T cell receptor-mediated cytotoxic T lymphocyte activation.
Recognition by CD8+ cytotoxic T lymphocytes (CTLs) of antigenic peptides bound to major histocompatibility class (MHC) I molecules on target cells leads to sustained calcium mobilization and CTL degranulation resulting in perforin-dependent killing. We report that beta1 and beta3 integrin-mediated adhesion to extracellular matrix proteins on target cells and/or surfaces dramatically promotes CTL degranulation. CTLs, when adhered to fibronectin but not CTL in suspension, efficiently degranulate upon exposure to soluble MHC.peptide complexes, even monomeric ones. This adhesion induces recruitment and activation of the focal adhesion kinase Pyk2, the cytoskeleton linker paxillin, and the Src kinases Lck and Fyn in the contact site. The T cell receptor, by association with Pyk2, becomes part of this adhesion-induced activation cluster, which greatly increases its signaling.
Doucey
Marie-Agnès
MA
Institute for Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland. ma_doucey@hotmail.com
Legler
Daniel F
DF
Faroudi
Mustapha
M
Boucheron
Nicole
N
Baumgaertner
Petra
P
Naeher
Dieter
D
Cebecauer
Marek
M
Hudrisier
Denis
D
Rüegg
Curzio
C
Palmer
Ed
E
Valitutti
Salvatore
S
Bron
Claude
C
Luescher
Immanuel F
IF
D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism; D020013:Calcium Signaling; D002448:Cell Adhesion; D015550:Cell Degranulation; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005353:Fibronectins / Q000378:metabolism; D051418:Focal Adhesion Kinase 2; D006183:H-2 Antigens / Q000235:genetics / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism*; D039661:Integrin beta3 / Q000378:metabolism*; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D051379:Mice; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D016827:CD8 Antigens; D003598:Cytoskeletal Proteins; D005353:Fibronectins; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D019012:Integrin beta1; D039661:Integrin beta3; D051419:Paxillin; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; C496062:Pxn protein, mouse; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C494960:Fyn protein, mouse; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; C496053:Ptk2b protein, mouse