Interactions with self–major histocompatibility complex molecules on dendritic cells (DCs) are important for the survival of mature CD4⁺ T cells. We have followed the DC-mediated signal from the T cell surface to the nucleus and identified a pattern of activation that correlates with increased in vitro survival. This response is induced exclusively by DCs and is likely associated with a modulation of the T cell activation threshold. We have also found that DC-mediated activation results in antigen-independent cytokine gene expression, which points to a new role for DCs in shaping the cytokine milieu. Such antigen-independent activation of T cells may play a role in protective immunity, but may also induce and perpetuate autoimmune states such as multiple sclerosis.