Soluble CTLA-4 regulates immune homeostasis and promotes resolution of inflammation by suppressing type 1 but allowing type 2 immunity

IF 25.5 1区医学 Q1 IMMUNOLOGY

Immunity Pub Date : 2025-03-31 DOI:10.1016/j.immuni.2025.03.004

Motonao Osaki, Shimon Sakaguchi

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Abstract

Cytotoxic T-lymphocyte-associated antigen -4 (CTLA-4) is a co-inhibitory receptor that restricts T cell activation. CTLA-4 exists as membrane (mCTLA-4) and soluble (sCTLA-4) forms, but the key producers, kinetics, and functions of sCTLA-4 are unclear. Here, we investigated the roles of sCTLA-4 in immune regulation under non-inflammatory and inflammatory conditions. Effector regulatory T (Treg) cells were the most active sCTLA-4 producers in basal and inflammatory states, with distinct kinetics upon T cell receptor (TCR) stimulation. We generated mice specifically deficient in sCTLA-4 production, which exhibited spontaneous activation of type 1 immune cells and heightened autoantibody/immunoglobulin E (IgE) production. Conversely, mCTLA-4-deficient mice developed severe type 2-skewed autoimmunity. sCTLA-4 blockade of CD80/86 on antigen-presenting cells inhibited T helper (Th)1, but not Th2, differentiation in vitro. In vivo, Treg-produced sCTLA-4, suppressed Th1-mediated experimental colitis, and enhanced wound healing but hampered tumor immunity. Thus, sCTLA-4 is essential for immune homeostasis and controlling type 1 immunity while allowing type 2 immunity to facilitate resolution in inflammatory conditions.

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可溶性CTLA-4调节免疫稳态，通过抑制1型而允许2型免疫来促进炎症的解决

细胞毒性T淋巴细胞相关抗原-4 （CTLA-4）是一种限制T细胞活化的共抑制受体。CTLA-4以膜（mCTLA-4）和可溶性（sCTLA-4）两种形式存在，但主要的产生物、动力学和功能尚不清楚。在这里，我们研究了sCTLA-4在非炎症和炎症条件下的免疫调节中的作用。在基础状态和炎症状态下，效应调节性T细胞（Treg）是最活跃的sCTLA-4产生细胞，在T细胞受体（TCR）刺激下具有不同的动力学。我们产生了sCTLA-4产生特异性缺陷的小鼠，这些小鼠表现出1型免疫细胞的自发激活和自身抗体/免疫球蛋白E （IgE）产生的增加。相反，mctla -4缺陷小鼠出现严重的2型倾斜自身免疫。sCTLA-4阻断抗原呈递细胞的CD80/86可抑制体外辅助性T (Th)1的分化，但不抑制Th2的分化。在体内，treg产生sCTLA-4，抑制th1介导的实验性结肠炎，促进伤口愈合，但阻碍肿瘤免疫。因此，sCTLA-4对于免疫稳态和控制1型免疫至关重要，同时允许2型免疫促进炎症条件下的解决。

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来源期刊

Immunity 医学-免疫学

CiteScore

49.40

自引率

2.20%

发文量

205

审稿时长

6 months

期刊介绍： Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.