<p>Self-DNA sensing by the immune system was discovered more than half a century ago. It has emerged as a key factor in the development of cancer, autoimmune diseases and many inflammatory diseases. While the innate immune response has been extensively studied, how self-DNA drives adaptive immune responses, particularly those mediated by T cells, has only been gradually unraveled over the past decade. In fact, adaptive DNA immunity plays a role in key cellular activities relevant to physiology and disease, containing cell functional activation, proliferation, differentiation, senescence and apoptosis. Herein, we review the latest research of self-DNA induced T cell immune response from the point of the origin of self-DNA, the mechanism of T cell responses to self-DNA and the fate of T cells. We also summarize how these cellular maneuvers influence disease outcome in mammalian cells, providing an overview of the expanding landscape of self-DNA-evoked T cell immunity.</p>