The type 2 TNF receptor plays a critical role in the activation of Tregs in vivo. (34.3)

Abstract

Abstract Recent studies suggest that regulatory T cells (Tregs) exhibit functional and phenotypic plasticity dependent on the local cytokine milieu. Previous reports have shown that TNF-α stimulates Treg proliferation in vitro and that the type 2 TNF receptor (TNFR2) is expressed on a subset of Tregs with increased in vitro function. We now report that TNFR2 is up-regulated on all activated Tregs and is required for normal Treg suppression in vivo and optimal maintenance of Foxp3 in vitro. Using a model of colitis, wild type (WT) or TNFR2-/- Tregs were transferred into RAG-1-/- mice together with WT CD4+CD25- effector T cells (Teff). TNFR2-/- Tregs were significantly less capable of suppressing both IFNg production and colitis. Surprisingly, TNFR2-/- and WT Tregs, activated in vitro prior to transfer, as well as iTregs generated in-vitro from WT or TNFR2-/- Teff, were identical in suppressive capacity in vivo. These results suggest that TNFR2 plays a critical role in the initial activation of Tregs in vivo. To determine if TNFR2 is involved in the stability of Tregs, Foxp3-GFP Tregs were sorted into TNFR2 High and TNFR2 Low populations and stimulated in-vitro with CD3ab and IL-2. After 3 days, the TNFR2 low population contained significantly fewer Foxp3+ cells than the TNFR2 high population. Overall, our results suggest that TNF-α signaling through TNFR2 may play a critical role in the initial activation of Tregs and may be an important factor for maintaining phenotypic stability.