A novel TNFR2 agonist peptide for the expansion of CD4+Foxp3+ regulatory T cells

作者：Ping Liao, Zhonghao Chen, Yang Gao, Yang Yang, Yibo Chen, Jiamin Chen, Yiru Wang, Chon‐Kit Chou, Shaoyi Zhang, Xin Chen · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1696587 · 被引用次数：1 · 研究领域：T-cell and B-cell Immunology、Psoriasis: Treatment and Pathogenesis、Immune Response and Inflammation

CD4 + Foxp3 + regulatory T cells (Tregs) are essential for maintaining immune tolerance, and selective expansion of Tregs via TNFR2 signaling represents a promising therapeutic approach for autoimmune and inflammatory diseases. Here, we report the identification and characterization of UMR2-705, a novel TNFR2 agonist discovered through phage display screening. In vitro , peptide UMR2–705 selectively promoted Treg proliferation in both human peripheral blood mononuclear cells and murine CD4 + T cell cultures without stimulating conventional CD4 + effector or CD8 + T cells. This effect was abrogated by the TNFR2-specific blocking antibody TR75-54.7, indicating its TNFR2 dependency. In vivo , administration of peptide UMR2–705 expanded Tregs in murine spleen and lymph nodes, attenuated LPS-induced systemic cytokine release (IL-6, TNF-α, IL-17A) in serum, and preserved immune homeostasis during systemic inflammation through TNFR2-dependent modulation of the regulatory compartment. Transcriptomic profiling revealed activation of TNFR2-associated signaling and upregulation of immune-regulatory pathways. These findings identify peptide UMR2–705 as a selective, peptide-based TNFR2 agonist with potent Treg-expanding and anti-inflammatory activities, supporting its potential as a therapeutic candidate for autoimmune and inflammatory disorders.