Factors regulating apoptosis and homeostasis of CD4+CD25highFOXP3+ regulatory T cells are new therapeutic targets

CD4(+)CD25(high)Foxp3(+) regulatory T cells (Tregs), as an active mechanism of immune suppression, have been targeted due to their tremendous therapeutic potentials to prevent autoimmune diseases, transplant rejection, and to inhibit progression of tumors and chronic viral diseases. In last twelve years, substantial molecular differences between homeostasis of Tregs and that of other subsets of T cells and some factors specific in regulation of Treg survival have been characterized. In this overview we focus on panoramic reviewing of 91 factors, pathways and drugs, both well-characterized and newly defined, regarding the survival and homeostasis of Tregs in the following sections: 2: Tregs, an essential mechanism of immune tolerance; 3: nTregs, aTregs and other regulatory T cells; 4: co-stimulation receptor signaling; 5: innate immunity and Toll-like receptor (TLR) signaling; 6: effects of cytokines and hormones; 7: transcription factors in regulation of Tregs; 8: Treg intracellular signaling and IL-4 cytokines exert their protective function on CD4+ T cells in the presence of soluble CD4 ligands, shows that they are able to reduce susceptibility to Bax-mediated apoptosis but not to CD95-dependent apoptotic pathways (289). A recent report from our laboratory showed that Tregs express higher levels of Bax than CD4+CD25- T cells (278). Our results further demonstrated for the first time that removal of Tregs via a Bax-dependent apoptosis pathway significantly enhances anti-self-tumor antigen immune responses (278), which points out that apoptosis pathway of Tregs is a new therapeutic target for treatment of immune related diseases.