Our studies of Tregs have revealed that TNF by acting on the TNFR2 receptor, which is 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. Furthermore, TNF interactions with TNFR2 also stabilizes the CD4+ FOXP3+ Tregulatory cell phenotype in inflammatory sites. One clarification of these unexpected effects of TNF is based on our data showing that TNF by activating Teffector cells also induces them to express TNFR2 and to become more resistant to the suppressive effects of Tregs. Thus, activated T cells at inflammatory sites or in autoimmune states can prevail over the suppressive effects of Tregs. However, as inflammation subsides in healing wounds or in noninflamed tumors Tregs prevail. Most tumor infiltrating T cells (TIL's) actually convert 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 anti-tumor responses to become evident. Consequently, our preliminary results show that anti-TNF reduced the growth of mouse Lewis lung and breast (4T1) tumors. Thus, by identifying better means of countering Tregs, we may be able to enhance antitumor responses to tumor vaccines.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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