Modulation of Regulatory T Cell Activity by TNF Receptor Type II-Targeting Pharmacological Agents

Abstract

There is now compelling evidence that tumor necrosis factor (TNF)–TNF receptor type II (TNFR2) interaction plays a decisive role in the activation, expansion, and phenotypical stability of suppressive CD4+Foxp3+ regulatory T cells (Tregs). In an effort to translate this basic research finding into a therapeutic benefit, a number of agonistic or antagonistic TNFR2-targeting biological agents with the capacity to activate or inhibit Treg activity have been developed and studied. Recent studies also show that thalidomide analogs, cyclophosphamide, and other small molecules are able to act on TNFR2, resulting in the elimination of TNFR2-expressing Tregs. In contrast, pharmacological agents, such as vitamin D3 and adalimumab, were reported to induce the expansion of Tregs by promoting the interaction of transmembrane TNF (tmTNF) with TNFR2. These studies clearly show that TNFR2-targeting pharmacological agents represent an effective approach to modulating the function of Tregs and thus may be useful in the treatment of major human diseases such as autoimmune disorders, graft-versus-host disease (GVHD), and cancer. In this review, we will summarize and discuss the latest progress in the study of TNFR2-targeting pharmacological agents and their therapeutic potential based on upregulation or downregulation of Treg activity.

Re-Examining the Role of TNF in MS Pathogenesis and Therapy

“…This wide cellular expression in the immune system makes TNF a crucial regulator of autoimmune responses, which explains the development of a plethora of anti-TNF drugs for autoimmune disorders (see later paragraph 4). Due to the complexity of the immune responses mediated by TNF and for the aim of this review, we provide a brief overview on TNF role in T cell-subset function and we refer the reader to more detailed reviews on this topic [ 37 , 38 ].…”

“…It has recently become apparent that TNF can exert a strong activity on CD4+ Tregs, which are a subset of CD4+ T cells that help to prevent or treat autoimmunity by maintaining self-tolerance, immune homeostasis, and suppression of cytotoxic T cells [ 50 ]. Mounting evidence indicate a crucial role of TNFR2 in Treg biology, supporting the development of drugs specifically targeting TNFR2 to potentiate or weaken Treg functions in autoimmune disorders [ 38 ]. Indeed, TNFR2 is upregulated in activated Tregs [ 41 ] and can promote itself the proliferation and expansion of Tregs [ 51 , 52 ].…”

A New Venue of TNF Targeting

“…The opposite approach that is currently investigated implies TNFR2 activation to stimulate the TNFR2-mediated protective pathways in autoimmunity and neurodegenerative diseases [352]. It has been suggested that this strategy might be superior to TNFR1 antagonism because of the restricted cellular expression of TNFR2.…”

Efficacy of infliximab, cyclosporine and tacrolimus on ulcerative colitis

“…[ 11 – 13 ] Antitumor necrosis factor α (Anti-TNF-α) antibodies interfere with endogenous TNF-α activity via binding to human TNF-α what plays a decisive role in activation, expansion, and phenotypical stability of T cells. [ 10 , 14 , 15 ] Thus, both calcineurin inhibitors and anti-TNF-α antibodies have been considered for UC therapy. [ 4 ]…”