DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease

Abstract

CD4Foxp3 regulatory T cells (Treg) are a subpopulation of T cells, which regulate the immune system and enhance immune tolerance after transplantation. Donor-derived Treg prevent the development of lethal acute graft-versus-host disease (GVHD) in murine models of allogeneic hematopoietic stem cell transplantation. We recently demonstrated that a single treatment of the agonistic antibody to DR3 (death receptor 3, αDR3) to donor mice resulted in the expansion of donor-derived Treg and prevented acute GVHD, although the precise role of DR3 signaling in GVHD has not been elucidated. In this study, we comprehensively analyzed the immunophenotype of Treg after DR3 signal activation, demonstrating that DR3-activated Treg (DR3-Treg) had an activated/mature phenotype. Furthermore, the CD25Foxp3 subpopulation in DR3-Treg showed stronger suppressive effects in vivo. Prophylactic treatment of αDR3 to recipient mice expanded recipient-derived Treg and reduced the severity of GVHD, whereas DR3 activation in mice with ongoing GVHD further promoted donor T-cell activation/proliferation. These data suggest that the function of DR3 signaling was highly dependent on the activation status of the T cells. In conclusion, our data demonstrated that DR3 signaling affects the function of Treg and T-cell activation after alloantigen exposure in a time-dependent manner. These observations provide important information for future clinical testing using human DR3 signal modulation and highlight the critical effect of the state of T-cell activation on clinical outcomes after activation of DR3.

Death receptor 3 signaling enhances proliferation of human regulatory T cells

“…Mouse studies reported an increase in Treg frequency in vivo upon activation of DR3 using agonistic antibodies or a TL1A‐Ig fusion protein . Our findings regarding DR3 expression and signaling in human Tregs prompted us to evaluate whether DR3 activation also enhanced proliferation of human Tregs.…”

“…Our findings also substantially extend the aforementioned mouse studies regarding the mechanism of DR3 activation. Most in vivo studies on DR3 activation in Tregs used agonistic anti‐DR3 antibodies instead of the endogenous ligand TL1A . In context of antibody‐mediated activation of TNFRSF members, the Fcγ receptor binding of agonists may be friend or foe: on one hand necessary to unleash the full agonistic potential, on the other hand prone to induce effector activities such as antibody‐dependent cellular cytotoxicity (reviewed in Ref.…”

Acute Graft-versus-Host Disease — Biologic Process, Prevention, and Therapy

“…Novel targets include kinase inhibitors that block the protein serine/threonine kinase ROCK1 111 , Aurora kinase A 112 , MEK 113 , and others (Supplemental appendix and Figure 3B). Strategies being investigated to improve Treg efficacy by in vivo Treg expansion in mouse models include TNFRSF25 (DR3) stimulation using a fusion protein to ligate the receptor 114 , agonistic DR3 antibody 115 and agonistic TNFR2 antibody 116 .…”

Multifaceted death receptor 3 signaling—promoting survival and triggering death

“…Importantly, the graft-versus-malignancy effect of transplanted donor T cells was preserved. A very recent publication confirmed these findings and elaborated on the phenotype of anti-DR3-treated Tregs in further detail [64]. DR3 stimulation caused a distinct gene expression profile and upregulation of activation markers on Tregs, functionally resulting in enhanced suppressive capacity.…”

“…A DR3-specific agonistic antibody triggered Treg proliferation and attenuated cardiac allograft rejection in fully major histocompatibility complex (MHC)-mismatched ectopic heart transplants [62]. In line with this, a number of studies recently demonstrated that DR3-mediated proliferation of Tregs attenuated GVHD in mice after allogeneic hematopoietic stem cell transplantation (HSCT) or autologous bone marrow transplantation [60,61,63,64]. Treatment of donor mice with an agonistic anti-DR3 antibody induced Treg proliferation and transfer of DR3-expanded Tregs together with hematopoietic stem cells (HSC) attenuated disease activity in a MHC major mismatch GVHD model [63].…”