About this Research Topic
CD4+FoxP3+ regulatory T cells (Tregs) play an indispensable role in the maintenance of immune homeostasis and prevention of autoimmune diseases, and represent a major cellular mechanism of tumor immune evasion. Targeting of Tregs has great potential in the treatment of some major human diseases, including autoimmunity, transplant rejection, GvHD, and cancer, and are critical controllers of immunity to infectious pathogens. It is expected they will also be central to the control of allergic and inflammatory diseases. Understanding the biological pathways crucial for the regulation of Treg activity is a prerequisite for harnessing the immense therapeutic potential of Tregs. TNF is generally believed to be a master pro-inflammatory cytokine, and anti-TNF therapy has become a mainstay treatment for some autoimmune diseases. However, experimental evidence indicates that TNF preferentially activates Tregs, resulting in the expansive proliferation, phenotypic stability, and enhanced suppressive capacity of these immune suppressors. This effect of TNF is mediated by TNFR2, which is preferentially expressed by human and mouse Tregs. Furthermore, expression of TNFR2 is able to identify the most suppressive subset of Tregs. Although counterintuitive and contradictory to earlier reports, these findings have been supported by increasing experimental evidence from both human and mouse studies. These recent studies revealing the Treg-promoting effect of TNF not only leads to the redefinition of the immunological biology of this pleiotropic cytokine, they are also helpful in designing novel therapies in the treatment of cancer, autoimmune diseases, and GvHD, as well as enhancing current vaccines and immunomodulators. In this article collection, current knowledge on the cellular and molecular aspects of the Treg-stimulatory effect of the TNF-TNFR2 pathway will be discussed.
An insight of the physiological and pathological roles of such effects of TNF in an inflammatory reaction and immune response will be provided. The seemingly contradictory Treg-promoting effect of TNF and immunosuppressive effect of anti-TNF therapy will be analyzed. Recent efforts to translate such discoveries into therapeutic benefits will be introduced. The novel strategies in the treatment of cancer and GvHD, by down- or up-regulation of Treg activity through targeting TNFR2, will be highlighted. In addition to Tregs, TNFR2 has also been found to play a key role in the accumulation and immunosuppressive function of myeloid-derived suppressive cells (MDSCs) and Mesenchymal stem cells (MSCs). Therefore, the current understanding of the role of TNF-TNFR2 signal in other type of immunosuppressive cells, as well as its clinical and therapeutic implications, will also be considered.
Thus, this Research Topic summarizes the latest knowledge on the decisive role of TNF-TNFR2 signaling on the biology of Tregs and other immunosuppressors, and analyzes its implications in the treatment of cancer and harmful inflammatory responses. We aim to bring together the scientists in both the basic research community as well as in the clinical research community for an in-depth discussion, which will hopefully result in the identification of a future direction for a more physiologically relevant translational study. To this end, we encourage the submission of primary research reports and review articles on the role of TNF-TNFR2 signaling in immunosuppressive function of Tregs, MDSCs and MSCs, or other immune cell types. The views and discussion on the development of novel therapeutics for up- or down-regulation immunity by targeting TNF-TNFR2 interactions, are also welcome.
Keywords: TNF, TNFR2, Tregs, immunotherapy, cancer, autoimmune diseases, MSCs, MDSCs, infectious disease, allergy, asthma
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