Exemplifying complexity of immune suppression by a “canonical” speech: A glimpse into TNFRSF‐activated signaling pathways in Treg cells

Regulatory T (Treg) cells are crucial mediators of immune tolerance suppressing self-reactive T cells and preventing autoimmune diseases. Besides activation of the T cell receptor (TCR), empowerment of Treg cell functions requires co-accessory signals, such as those released by the TNF receptor superfamily (TNFRSF) that, however, can also promote immunostimulatory responses when engaged by effector T cells. In this issue of European Journal of Immunology, Lubrano di Ricco et al. [Eur. J. Immunol. 2020. 50: 972-985] have taken a closer look at the important question of the functional meaning of TNFRSF-activated signaling pathways in Treg cells. They have demonstrated that costimulation by TNFR2, 4-1BB, GITR, DR3, but not OX40 in mouse Foxp3+ Treg cells activates the same and unique signaling pathway, i.e., canonical NF-κB, which in turn leads to Foxp3 gene upregulation, cell expansion in vitro and in vivo, and suppressive activity in an experimental model of colitis. Moreover, induction of markers of T helper 2 (Th2) and Th17 as well as of genes encoding proteins involved in noncanonical NF-κΒ was also observed. We here discussed how these findings further highlight the emerging concept of Treg cell plasticity in immune tolerance.