Our studies of Tregs have revealed that TNF by acting on the TNFR2 receptor, which is most highly expressed by Tregs, unexpectedly results in their proliferative expansion and functional activation both in mice and in man. In view of the well-known proinflammatory effects of TNF, our data showing that TNF in a more delayed manner can also down-regulate immune responses is rather surprising. Furthermore, TNF together with IL-2 up-regulates the cell surface expression of TNFR2 and also of 4-1BB and OX-40 receptors. Stimulation of these three TNF superfamily (TNFRSF) receptors expands the Treg population. Thus, TNF amplifies its stimulatory effect on Tregs by inducing 3 TNFRSF members. In addition, other mediators can upregulate Tregs. For example we have shown this past year that progranulin, an immunosuppressive growth factor, promotes TNF-TNFR2 interactions on Treg cells. Furthermore, TNF interactions with TNFR2 also stabilizes the CD4+FOXP3+ T regulatory cell phenotype at inflammatory sites. One clarification of these unexpected effects of TNF is based on our data showing that TNF by activating Teffector cells also induce them to express TNFR2 and to become more resistant to the suppressive effects of Tregs. Thus activated inflammatory sites can prevail over the suppressive effects of Tregs. However, as inflammation subsides in healing wounds or in non-inflamed tumors Tregs prevail. About 50% tumor infiltrating T cells (TIL's) develop into Tregs and express TNFR2. They are activated by tumor-derived TNF to be even more immunosuppressive than Tregs in peripheral lymphoid tissues. Suppression of Tregs should enable more effective host antitumor responses to become evident. This hypothesis was tested by us by treating mice bearing 4T1 mammary tumors with neutralizing anti-TGFbeta and cyclophosphamide, which suppresses Tregs thus promoting cell mediated immunity. This resulted in 80% of the mice becoming tumor free and preferentially resisting a subsequent 4T1 tumor challenge. These treated mice developed considerable infiltration of their tumors by IFNgamma producing rather than Treg TIL cells and had reduced numbers of MDSC in their spleens and tumors. These finding suggest that this therapy enabled the mice to develop considerable antitumor immunity. This past year we also reported that Tregs are rather """"""""plastic"""""""" in nature and readily convert into Th17 cells under the influence of TGFbeta plus IL6. Since some Tregs produce TGFbeta, they can promote conversion of Tregs into Th17 cells. Conversely, Th17 cells as the most prolific producers of TNF are excellent promoters of Treg cell expansion and stabilizers of FoxP3 expression. Thus, TNFR2 expressing Tregs help Th17 cells and they are reciprocally stimulated by Th17 cells.
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