Stimulation via the T-cell receptor results in proliferation of naive T cells and activation-induced death of activated T cells. The expression of Fas ligand and activation-induced cell death are major mechanisms by which immune responses are modulated in the lung. Although it is known that the binding of integrin receptors to extracellular matrix proteins provides co-stimulatory signals to naive T cells, it is not clear whether these signals are critical for activated T cells. The activation and differentiation of T cells is marked by significant changes in integrin expression and affinity. To determine the role of integrin signaling in restimulation of activated T cells, we blocked integrin receptors with RGD peptides. Using murine activated CD4+ T cells and the T-cell hybridoma DO11.10, we found that RGD peptides inhibit tyrosine phosphorylation of CD3 epsilon-chain and ZAP-70, clustering of T-cell receptors, extracellular signal-regulated kinase mitogen-activated protein-kinase activation, and Fas ligand expression and prevent activation-induced cell death. We demonstrate that activated T cells are sensitive to integrin co-stimulation and that integrin receptors are required for the successful restimulation of activated T cells. This indicates that matrix proteins may play a major role in regulating T-cell-mediated immune responses in the lung.