The onset of autoimmunity in experimental rodent models and patients frequently correlates with a lymphopenic state. In this condition, the immune system has evolved compensatory homeostatic mechanisms that induce quiescent naive T cells to proliferate and differentiate into memory-like lymphocytes even in the apparent absence of antigenic stimulation. Because memory T cells have less stringent requirements for activation than naive cells, we hypothesized that autoreactive T cells that arrive to secondary lymphoid organs in a lymphopenic environment could differentiate and bypass the mechanisms of peripheral tolerance such as those mediated by self-antigen cross-presentation. Here, we show that lymphopenia-driven proliferation and differentiation of potentially autoreactive CD8⁺ T cells into memory-like cells is not sufficient to induce self-reactivity against a pancreatic antigen. Induction of an organ-specific autoimmunity required antigen-specific CD4⁺ T cell help. Notably, we found that this function could be accomplished by memory-like CD4⁺ T cells generated in vivo through lymphopenia-induced proliferation. These helper cells promoted the further differentiation of memory-like CD8⁺ T cells into effectors in response to antigen cross-presentation, resulting in their migration to the tissue of antigen expression where autoimmunity ensued. Thus, the cooperation of self-reactive memory-like CD4⁺ and CD8⁺ T cells under lymphopenic conditions overcomes cross-tolerance resulting in autoimmunity.