Potent costimulation of effector T lymphocytes by human collagen type I

Purified, resting peripheral blood T lymphocytes were previously reported t o undergo beta (1) integrin-dependent activation when cultured with anti-CD 3 mAb coimmobilized with fibronectin, but not type I collagen. However, the extravascular T cells that encounter immobilized extracellular matrix prot eins and are involved in disease pathogenesis have different properties fro m resting peripheral blood cells, In this study, we confirm that resting CD 4(+) and CD8(+) T cells from peripheral blood are costimulated by immobiliz ed fibronectin, but not type I collagen. In contrast, Ag- or mitogen-stimul ated CD4(+) and CD8(+) T cell lines, used as models of the effector cells i nvolved in disease, are more potently costimulated by type I collagen than fibronectin. The collagen-induced effects are similar in assays with serum- free medium and in more physiological assays in which anti-CD3 mAb is repla ced by a threshold concentration of Ag and irradiated autologous PBMC as AP C. The responses are beta (1) integrin dependent and mediated largely by ve ry late Ag (VLA) 1 and 2, as shown by their up-regulation on the T cell lin es as compared with freshly purified resting PBL, and by the effects of blo cking mAb, Reversed phase HPLC located the major costimulatory sequence(s) in the alpha1 chain of type I collagen, the structure of which was confirme d by amino acid sequencing, The results demonstrate the potential importanc e of type I collagen, an abundant extracellular matrix protein, in enhancin g the activation of extravascular effector T cells in inflammatory disease, and point to a new immunotherapeutic target.