Autoimmune diseases decrease life expectancy and quality of life for millions of women and men. Although treatments can slow disease progression and improve quality of life, all currently available drugs have adverse effects and none of them are curative; therefore, requiring patients to take immunosuppressive drugs for the remainder of their lives. A curative therapy that is safe and effective is urgently needed. We believe that therapies promoting the in vivo expansion of regulatory T cells (Tregs) or injection of in vitro expanded autologous/heterologous Tregs (cellular therapy) can alter the natural history of autoimmune diseases. In this review, we present data from murine and human studies suggesting that 1) glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) plays a crucial role in thymic Treg (tTreg) differentiation and expansion; 2) GITR plays a crucial role in peripheral Treg (pTreg) expansion; 3) in patients with Sjögren syndrome and systemic lupus erythematosus, CD4+GITR+ pTregs are expanded in patients with milder forms of the disease; and 4) GITR is superior to other cell surface markers to differentiate Tregs from other CD4+ T cells. In this context, we consider two potential new approaches for treating autoimmune diseases consisting of the in vivo expansion of GITR+ Tregs by GITR-triggering drugs and in vitro expansion of autologous or heterologous GITR+ Tregs to be infused in patients. Advantages of such an approach, technical problems, and safety issues are discussed. © 2014 Elsevier B.V.

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