Signaling pathway(s) of TNFR2 required for the immunoregulatory effect of CD4+Foxp3+ regulatory T cells

CD4+Foxp3+ regulatory T cells (Tregs), a subpopulation of CD4+ T cells, are engaged in maintaining the periphery tolerance and preventing autoimmunity. Recent studies showed that tumor necrosis factor receptor 2 (TNFR2) is preferentially expressed by Tregs and the expression of this receptor identifies the maximally suppressive Tregs. That is, TNFR2 is a liable phenotypic and functional surface marker of Tregs. Moreover, TNF activates and expands Tregs through TNFR2. However, it is very interesting which signaling pathway(s) of TNFR2 is required for the inhibitory effect of Tregs. Compelling evidence shows three TNFR2 signaling pathways in Tregs, including NF-κB, MAPK and PI3K-Akt pathways. Here, we summarize and discuss the latest progress in the studies on the downstream signaling pathways of TNF-TNFR2 for controlling Treg homeostasis, differentiation and proliferation.