A model for the role of CD4+ T cells in the pathogenesis of chronic inflammation. Antigen drive predominates during the early phase of inflammatory responses ('antigen mode'). In a nonsusceptible host, the immune response resolves through mechanisms such as activation-induced cell death and/or the production of immunoregulatory cytokines. In the susceptible host, additional T cells are recruited to sites of inflammation through bystander activation, or by stimulation with self antigens released from inflamed tissues. As the inflammatory process progresses, chronic cytokine production induces profound nondeletional T-cell hyporesponsiveness. Hyporesponsive T cells function as effector cells and sustain the chronic inflammatory process through predominantly antigen independent mechanisms ('inflammation mode'). It is proposed that by reversing T-cell hyporesponsiveness, antigen-dependent responses that serve to regulate the inflammatory process (e.g. through expression of immunoregulatory cytokines) are restored.