The role of FOXP3⁺ regulatory T cells in human autoimmune and inflammatory diseases

CD4⁺ regulatory T cells (T_reg ) expressing the forkhead box protein 3 (FOXP3) transcription factor (T_regs ) are instrumental for the prevention of autoimmune diseases. There is increasing evidence that the human T regulatory population is highly heterogeneous in phenotype and function. Numerous studies conducted in human autoimmune diseases have shown that T_reg cells are impaired either in their suppressive function, in number, or both. However, the contribution of the FOXP3⁺ T_reg subpopulations to the development of autoimmunity has not been delineated in detail. Rare genetic disorders that involve deficits in T_reg function can be studied to develop a global idea of the impact of partial or complete deficiency in a specific molecular mechanism involved in T_reg function. In patients with reduced T_reg numbers (but no functional deficiency), the expansion of autologous T_reg cells could be a suitable therapeutic approach: either infusion of in-vitro autologous expanded cells, infusion of interleukin (IL)-2/anti-IL-2 complex, or both. T_reg biology-based therapies may not be suitable in patients with deficits of T_reg function, unless their deficit can be corrected in vivo/in vitro. Finally, it is critical to consider the appropriate stage of autoimmune diseases at which administration of T_reg cellular therapy can be most effective. We discuss conflicting data regarding whether T_reg cells are more effectual at preventing the initiation of autoimmunity, ameliorating disease progression or curing autoimmunity itself.