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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010707-08
Application #
8763180
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2013
Total Cost
$389,564
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Zaragoza, Bruno; Chen, Xin; Oppenheim, Joost J et al. (2016) Suppressive activity of human regulatory T cells is maintained in the presence of TNF. Nat Med 22:16-7
Hamano, Ryoko; Wu, Xueqiang; Wang, Yitao et al. (2014) Characterization of MT-2 cells as a human regulatory T cell-like cell line. Cell Mol Immunol :
Hu, Ya; Xiao, Haitao; Shi, Tingchen et al. (2014) Progranulin promotes tumour necrosis factor-induced proliferation of suppressive mouse CD4⁺ Foxp3⁺ regulatory T cells. Immunology 142:193-201
Zhou, Qiong; Hu, Ya; Howard, O M Zack et al. (2014) In vitro generated Th17 cells support the expansion and phenotypic stability of CD4(+)Foxp3(+) regulatory T cells in vivo. Cytokine 65:56-64
Chen, Xin; Wakefield, Lalage M; Oppenheim, Joost J (2014) Synergistic antitumor effects of a TGFβ inhibitor and cyclophosphamide. Oncoimmunology 3:e28247
Chen, Xin; Wu, Xueqiang; Zhou, Qiong et al. (2013) TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T. cell phenotype in the inflammatory environment. J Immunol 190:1076-84
Chen, Xin; Oppenheim, Joost J (2011) Contrasting effects of TNF and anti-TNF on the activation of effector T cells and regulatory T cells in autoimmunity. FEBS Lett 585:3611-8
Hamano, Ryoko; Huang, Jiaqiang; Yoshimura, Teizo et al. (2011) TNF optimally activatives regulatory T cells by inducing TNF receptor superfamily members TNFR2, 4-1BB and OX40. Eur J Immunol 41:2010-20
Chen, Xin; Oppenheim, Joost J (2011) Comment on "Interplay between TNF and regulatory T cells in a TNF-driven murine model of arthritis". J Immunol 187:1527; author reply 1527-8
Chen, Xin; Oppenheim, Joost J (2011) Resolving the identity myth: key markers of functional CD4+FoxP3+ regulatory T cells. Int Immunopharmacol 11:1489-96

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