Enhancement of activation-induced cell death by fibronectin in murine CD4+ CD8+ thymocytes.
Development of T cells in the thymus is achieved through the interactions of thymocytes with their microenvironments. This study focused on the function of fibronectin (FN), a major extracellular matrix molecule in the thymus, in the cell death induced by activation via the T-cell antigen receptor. FN alone did not increase cell death in murine thymocytes above the baseline level, but it significantly enhanced the cell death induced by fixed anti-CD3 monoclonal antibody (mAb), especially when a high concentration of anti-CD3 mAb was used. DNA fragmentation increased in parallel with cell death, indicating that cell death was a result of the apoptosis. Fluorescence-activated cell sorter (FACS) analysis revealed that the activation-induced cell death (AICD) caused by anti-CD3 mAb alone, or by a combination of anti-CD3 mAb and FN, occurred selectively in CD4+ CD8+ thymocytes. Very late activation antigen (VLA)-4 and VLA-5 are two major ligands to FN on thymocytes. The expression of both ligands was investigated at different stages of thymocyte development. VLA-4 was predominantly expressed at the CD4- CD8- stage, and thereafter the expression was reduced, whereas VLA-5 was constantly expressed during maturation. Furthermore, the enhancing effect by FN was inhibited in the presence of the Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) peptide but not in the presence of the connecting segment-1 (CS-1) peptide, suggesting that enhancement of AICD observed in CD4+ CD8+ thymocytes is mediated through VLA-5.
Takayama
E
E
Department of Parasitology, National Defense Medical College, Tokorozawa, Saitama 359, Japan.
Kina
T
T
Katsura
Y
Y
Tadakuma
T
T
D000818:Animals; D018926:Anti-Allergic Agents; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D002478:Cells, Cultured; D053938:DNA Fragmentation; D005353:Fibronectins / Q000494:pharmacology*; D005434:Flow Cytometry; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D017469:Receptors, Fibronectin / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*
D018926:Anti-Allergic Agents; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D005353:Fibronectins; D039041:Integrin alpha4beta1; D016023:Integrins; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell; D017469:Receptors, Fibronectin; D016201:Receptors, Lymphocyte Homing; C058161:glycyl-arginyl-glycyl-aspartyl-seryl-proline