Engagement of the alpha2beta1 integrin inhibits Fas ligand expression and activation-induced cell death in T cells in a focal adhesion kinase-dependent manner.
T-cell receptor (TCR)-mediated apoptosis, also known as activation-induced cell death (AICD), plays an important role in the control of immune response and in the development of T-cell repertoire. Mechanistically, AICD has been largely attributed to the interaction of Fas ligand (Fas-L) with its cell surface receptor Fas in activated T cells. Signal transduction mediated by the integrin family of cell adhesion receptors has been previously shown to modulate apoptosis in a number of different cell types; in T cells, integrin signaling is known to be important in cellular response to antigenic challenge by providing a co-stimulatory signal for TCR. In this study we demonstrate that signaling via the collagen receptor alpha2beta1 integrin specifically inhibits AICD by inhibiting Fas-L expression in activated Jurkat T cells. Engagement of the alpha2beta1 integrin with monoclonal antibodies or with type I collagen, a cognate ligand for alpha2beta1, reduced anti-CD3 and PMA/ionomycin-induced cell death by 30% and 40%, respectively, and the expression of Fas-L mRNA by 50%. Further studies indicated that the alpha2beta1-mediated inhibition of AICD and Fas-L expression required the focal adhesion kinase FAK, a known component in the integrin signaling pathways. These results suggest a role for the alpha2beta1 integrin in the control of homeostasis of immune response and T-cell development. (Blood. 2000;95:2044-2051)
Aoudjit
F
F
Cancer Research Center, The Burnham Institute, La Jolla, CA 92037, USA.
Vuori
K
K
D017209:Apoptosis; D017252:CD3 Complex / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D016923:Cell Death; D003094:Collagen / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D053938:DNA Fragmentation; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010957:Plasmids; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D038981:Receptors, Collagen; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D017252:CD3 Complex; D015815:Cell Adhesion Molecules; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D016023:Integrins; D007476:Ionophores; D008562:Membrane Glycoproteins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D038981:Receptors, Collagen; D015759:Ionomycin; D003094:Collagen; D003513:Cycloheximide; C113183:FAK-related nonkinase; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D013755:Tetradecanoylphorbol Acetate