Mutations of the gene encoding the cytoplasmic phosphatase PTPN22 confer an increased risk of autoimmunity in humans and mice, and this is associated with increased numbers of B and T cells. However Ptpn22−/− mice do not spontaneously develop autoimmunity. This study shows that such mice have an increased number of regulatory T (TReg) cells with increased immunosuppressive activity, which can prevent autoimmunity caused by Ptpn22−/− effector T cells in a mouse colitis model. Ptpn22−/− TReg cells secreted higher levels of interleukin-10 (IL-10) than wild-type TReg cells and had increased integrin-mediated adhesion downstream of T cell receptor signalling, both of which are crucial for TReg cell function. Therefore, PTPN22 regulates both effector and regulatory T cell populations to maintain homeostasis.