Factors regulating apoptosis and homeostasis of CD4+ CD25(high) FOXP3+ regulatory T cells are new therapeutic targets

Abstract

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 pathways; 9: drugs and potential therapeutics; and 10: Treg cell survival and death. We recently reported that removal of Tregs via a Bax-dependent apoptotic pathway significantly enhances anti-self antigen immune responses, which demonstrated for the first time the proof of principle that apoptosis of Tregs is a new therapeutic target. Therefore, continued characterization of Treg apoptosis and homeostasis pathways would further improve our understanding in regulation of immune responses by cytokines, hormones and drugs, and would also lead to development of new therapeutics.