Immunotherapy with antigen-processing independent T cell epitopes (apitopes) targeting autoreactive CD4 T cells has translated to the clinic and been shown to modulate progression of both Graves' disease and multiple sclerosis. The model apitope (Ac1-9[4Y]) renders antigen-specific T cells anergic while repeated administration induces both Tr1 and Foxp3 regulatory cells. Here we address why CD4 T cell epitopes should be designed as apitopes to induce tolerance and define the antigen presenting cells that they target . Furthermore, we reveal the impact of treatment with apitopes on CD4 T cell signaling, the generation of IL-10-secreting regulatory cells and the systemic migration of these cells. Taken together these findings reveal how apitopes induce tolerance and thereby mediate antigen-specific immunotherapy of autoimmune diseases.