CO-LIGATION OF ALPHA(4)BETA(1) INTEGRIN AND TCR RESCUES HUMAN THYMOCYTES FROM STEROID-INDUCED APOPTOSIS

Maturation of thymocytes represents a sequence of events during which thymocytes expressing TCR with moderate avidity for self antigen/MHC a re positively selected, whereas those with high or insufficient TCR av idity die.Glucocorticoids are produced intrathymically and can contrib ute to apoptosis of unselected thymocytes. Thymocytes differentiate in a close contact with epithelial cells, expressing vascular adhesion m olecule-1 (VCAM-1) and secreting glucocorticoids, with bone marrow-der ived macrophages, and with extracellular matrix containing fibronectin (FN) and collagen, Their contact with FN is mediated by alpha(4)beta( 1) and alpha(5)beta(1) integrins, We examined the contribution of TCR and integrin signaling to the survival of thymocytes from dexamethason e (Dex)-induced apoptosis, We demonstrate that FN and VCAM-1 (both of which bind alpha(4)beta(1) integrin), but not collagen, considerably a ugment TCR-mediated protection of thymocytes from Dex-induced apoptosi s, This 'survival' signal is transduced through the alpha(4)beta(1), b ut not through the alpha(5)beta(1) integrin, The observed protection f rom Dex-induced apoptosis correlated with an increase in bcl-2 protein levels. FN-alpha(4)beta(1) and VCAM-1-alpha(4)beta(1) engagement indu ced up-regulation bcl-2 protein, while alpha(5)beta(1) binding to FN i nduced a negative signal that was blocked by anti-alpha(5)beta(1) anti body, These data suggest that alpha(4)beta(1) integrin may contribute to protection of thymocytes with moderate avidity TCR from glucocortic oid-induced death during intrathymic maturation.