Fibronectin-associated Fas ligand rapidly induces opposing and time-dependent effects on the activation and apoptosis of T cells.
Recently, it has been shown that Fas ligand (FasL) interacts with the extracellular matrix (ECM) protein fibronectin (FN), and that the bound FasL retains its cytotoxic efficacy. Herein, we examined the ramifications of FasL-ECM protein interactions throughout a specific time period, in the absence or presence of additional activating molecules, assuming that these complexed interactions occur during inflammation. We found that exposure of purified human T cells to FN-associated recombinant FasL for as brief as 5-10 min at 0.1-100 ng/ml induced their adhesion in beta(1) integrin- and FasR-dependent manners while activating the intracellular protein kinase, Pyk-2. The FN-associated FasL stops the CXCL12 (stromal cell-derived factor 1alpha)-induced chemotaxis of T cells by inhibiting the chemokine-induced extracellular signal-regulated kinase signaling and cytoskeletal rearrangement. This short term exposure of T cells to the FN-bound FasL (1 ng/ml), which was followed by T cell activation via the CD3 complex, resulted in 1) increased secretion of IFN-gamma (measured after 24 h), and 2) enhanced T cell apoptosis (measured after 72 h). Thus, in the context of inflamed ECM and depending on the time after FasL activation, its concentration, and the nature of other contextual mediators, FasL initially retains effector T cells at sites of inflammation and, later, induces T cell apoptosis and return to homeostasis.
Zanin-Zhorov
Alexandra
A
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Hershkoviz
Rami
R
Hecht
Iris
I
Cahalon
Liora
L
Lider
Ofer
O
D000199:Actins / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D002448:Cell Adhesion / Q000276:immunology; D002464:Cell Migration Inhibition; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003599:Cytoskeleton / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000502:physiology; D053222:Fas Ligand Protein; D005353:Fibronectins / Q000378:metabolism*; D051418:Focal Adhesion Kinase 2; D006801:Humans; D019012:Integrin beta1 / Q000502:physiology; D007371:Interferon-gamma / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D016853:Muromonab-CD3 / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011485:Protein Binding / Q000276:immunology; D011493:Protein Kinase C / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D019014:fas Receptor / Q000378:metabolism* / Q000502:physiology
D000199:Actins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D018984:Epitopes, T-Lymphocyte; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D005353:Fibronectins; D019012:Integrin beta1; D007797:Laminin; D008024:Ligands; D008562:Membrane Glycoproteins; D016853:Muromonab-CD3; D019014:fas Receptor; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; D011493:Protein Kinase C