Co-ligation of α4β1 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 are positively selected, whereas those with high or insufficient TCR avidity die. Glucocorticoids are produced intrathymically and can contribute to apoptosis of unselected thymocytes. Thymocytes differentiate in a close contact with epithelial cells, expressing vascular adhesion molecule-1 (VCAM-1) and secreting glucocorticoids, with bone marrow-derived macrophages, and with extracellular matrix containing fibronectin (FN) and collagen. Their contact with FN is mediated by α4β1 and α5β1 integrins. We examined the contribution of TCR and integrin signaling to the survival of thymocytes from dexamethasone (Dex)-induced apoptosis. We demonstrate that FN and VCAM-1 (both of which bind α4β1 integrin), but not collagen, considerably augment TCR-mediated protection of thymocytes from Dex-induced apoptosis. This ‘survival’ signal is transduced through the α4β1, but not through the α5β1 integrin. The observed protection from Dex-induced apoptosis correlated with an increase in bcl-2 protein levels. FN–α4β1 and VCAM-1–α4β1 engagement induced up-regulation bcl-2 protein, while α5β1 binding to FN induced a negative signal that was blocked by anti-α5β1 antibody. These data suggest that α4β1 integrin may contribute to protection of thymocytes with moderate avidity TCR from glucocorticoid-induced death during intrathymic maturation.