Decoding TNF receptor superfamily control of CD4+Foxp3+ Regulatory T cell-mediated tolerance: implications for the treatment of graft‑versus‑host disease.

Allogeneic transplantation is a cornerstone treatment for hematologic malignancies and organ failure, yet its success is limited by graft-versus-host disease (GvHD) and allograft rejection. Conventional broad-spectrum immunosuppression compromises protective graft-versus-leukemia (GvL) effects and anti-infectious immunity, creating an urgent need for precision tolerance strategies. CD4+Foxp3+ regulatory T cell (Treg)-directed strategies offer a promising solution but expanding stable, functional Tregs ex vivo and in vivo remains challenging. Given the pivotal role of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) in Treg biology, this review aims to critically examine how its members control Treg function and how these pathways can be leveraged for Treg‑based therapies. We systematically analyze key TNFRSF members - TNFR2, OX40, CD40, Fas, CD27, 4-1BB, GITR, and DR3 - detailing their dichotomous roles in Treg function and translational potential. We highlight how agonism of TNFR2 or DR3 offers selective Treg expansion while preserving GvL activity, and how CD27 and 4-1BB serve as valuable markers for isolating highly suppressive Treg subsets. We further discuss translational challenges, including the paradoxical effects of OX40 and GITR, which can either enhance or impair Treg function depending on the inflammatory milieu, and the vulnerability of Tregs to Fas-mediated apoptosis during ex vivo expansion. We also discuss CD40-CD40L blockade as a complementary strategy to empower endogenous Tregs. By synthesizing current knowledge, this review provides a rational roadmap for using selective agonism, blockade, or phenotypic selection to bolster Treg‑based therapies for GvHD, offering practical information for both laboratory and clinical efforts to optimize Treg manufacturing and achieve durable tolerance.