斯坦福大学医学院K. Christopher Garcia小组的研究开发出了白细胞介素-2–TGFβ替代激动剂易诱导免疫耐受。该研究于2026年3月11日发表于国际一流学术期刊《自然》杂志上。

在这里，课题组人员设计了IL-2-TGFβ“替代”共激动剂，通过在IL-2和来自蠕虫寄生虫的低亲和力TGFβ模拟激动剂之间创建单链融合蛋白。这种IL-2-TGFβ替代物作为一种AND门控的协同激动剂，能够同时顺式激活IL-2–STAT5和TGFβ-SMAD2/3信号，特异性地在表达IL-2受体的T细胞中表达。IL-2-TGFβ替代激动剂可在卵清蛋白（OVA）和髓鞘少突胶质细胞糖蛋白（MOG）_35-55免疫小鼠外周血淋巴器官内诱导抗原特异性、功能性和稳定的pT_reg细胞。诱导的pT_reg细胞表现出效应物样的主动扩张状态，高表达RORγt，能够有效迁移和抑制肠道炎症。使用这种激动剂治疗可以有效地抑制过敏原诱导的过敏性炎症和自身抗原驱动的自身免疫性神经炎症的小鼠模型中的免疫激活，提示在体内诱导抗原特异性pT_reg细胞建立炎症、过敏和自身免疫性疾病的免疫耐受的策略。

据了解，CD4⁺调节性T细胞（T_reg细胞）对免疫耐受至关重要。外周诱导的T_reg细胞（pT_reg细胞）通过扩大T_reg细胞的反应性来响应不断变化的抗原环境，从而补充胸腺T_reg细胞。尽管TGFβ和IL-2在体外协同促进pT_reg细胞的发育，但它们在体内诱导pT_reg细胞生成的联合作用尚未被用于耐受免疫治疗。

附：英文原文

Title: Facile induction of immune tolerance by an interleukin-2–TGFβ surrogate agonist

Author: Sun, Qinli, Barrett, Alison K., Ogishi, Masato, Lyu, Huiyun, Jiang, Hua, Liu, Honghui, Zhao, Yang, Rodriguez, Grayson E., Tao, Pingdong, Obenaus, Matthias, Householder, Karsten D., Tang, Qizhi, Lanz, Tobias V., Garcia, K. Christopher

Issue&Volume: 2026-03-11

Abstract: CD4+ regulatory T cells (Treg cells) are essential for immune tolerance1. Peripherally induced Treg cells (pTreg cells) complement thymic Treg cells by broadening Treg cell reactivity in response to a changing antigenic landscape2. Although both TGFβ and IL-2 synergistically promote functional pTreg cell development in vitro3,4,5,6, their combined roles in inducing pTreg cell generation in vivo have not been exploited for tolerizing immunotherapy. Here we designed an IL-2–TGFβ ‘surrogate’ co-agonist by creating a single-chain fusion protein between IL-2 and a low-affinity TGFβ mimic agonist derived from a helminth parasite7. This IL-2–TGFβ surrogate functions as an AND-gated co-agonist and enabled simultaneous cis-activation of IL-2–STAT5 and TGFβ–SMAD2/3 signalling specifically in T cells that express IL-2 receptors. The IL-2–TGFβ surrogate agonist robustly induced antigen-specific, functional and stable pTreg cells in vivo within peripheral lymphoid organs in mice immunized with ovalbumin (OVA) and myelin oligodendrocyte glycoprotein (MOG)35–55. The induced pTreg cells display an effector-like, actively expanding state with high RORγt expression, enabling efficient migration and suppression of intestinal inflammation. Treatment with this agonist effectively quelled immune activation in mouse models of allergen-induced allergic inflammation and self-antigen-driven autoimmune neuroinflammation, suggesting a strategy for the induction of antigen-specific pTreg cells in vivo to establish immune tolerance in inflammatory, allergic and autoimmune diseases.

DOI: 10.1038/s41586-026-10208-0

Source: https://www.nature.com/articles/s41586-026-10208-0