Flotillin-2 dampens T cell antigen-sensitivity and functionality.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-11-05 DOI:10.1172/jci.insight.182328
Sookjin Moon, Fei Zhao, Mohammad N Uddin, Charles J Tucker, Peer Wf Karmaus, Michael B Fessler
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Abstract

T cell receptor (TCR) engagement triggers T cell responses, yet how TCR-mediated activation is regulated at the plasma membrane remains unclear. Here, we report that deleting the membrane scaffolding protein Flotillin-2 (Flot2) increases T cell antigen-sensitivity, resulting in enhanced TCR signaling and effector function to weak TCR stimulation. T cell-specific Flot2-deficient mice exhibited reduced tumor growth and enhanced immunity to infection. Flot2-null CD4+ T cells exhibited increased T helper 1 polarization, proliferation, Nur77 induction, and phosphorylation of ZAP70 and ERK1/2 upon weak TCR stimulation, indicating a sensitized TCR-triggering threshold. Single cell-RNA sequencing suggested that Flot2-null CD4+ T cells follow a similar route of activation as wild-type CD4+ T cells but exhibit higher occupancy of a discrete activation state under weak TCR stimulation. Given prior reports that TCR clustering influences sensitivity of T cells to stimuli, we evaluated TCR distribution with super-resolution microscopy. Flot2 ablation increased the number of surface TCR nanoclusters on naïve CD4+ T cells. Collectively, we posit that Flot2 modulates T cell functionality to weak TCR stimulation, at least in part, by regulating surface TCR clustering. Our findings have implications for improving T cell reactivity in diseases with poor antigenicity, such as cancer and chronic infections.

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Flotillin-2 可抑制 T 细胞的抗原敏感性和功能。
T细胞受体(TCR)啮合会触发T细胞反应,但TCR介导的活化如何在质膜上进行调控仍不清楚。在这里,我们报告了删除膜支架蛋白Flotillin-2(Flot2)可提高T细胞对抗原的敏感性,从而增强TCR信号传导和对弱TCR刺激的效应功能。T细胞特异性Flot2缺陷小鼠表现出肿瘤生长减少和感染免疫力增强。Flot2缺失的CD4+ T细胞在弱TCR刺激下表现出更高的T辅助细胞1极化、增殖、Nur77诱导以及ZAP70和ERK1/2磷酸化,表明TCR触发阈值敏感化。单细胞-RNA测序表明,Flot2-null CD4+ T细胞的活化途径与野生型CD4+ T细胞相似,但在弱TCR刺激下表现出更高的离散活化状态占据率。鉴于之前有报道称 TCR 聚集会影响 T 细胞对刺激的敏感性,我们用超分辨率显微镜评估了 TCR 的分布。Flot2 消融增加了幼稚 CD4+ T 细胞表面 TCR 纳米簇的数量。总之,我们认为 Flot2 至少部分地通过调节表面 TCR 聚类来调节 T 细胞对弱 TCR 刺激的功能。我们的发现对改善癌症和慢性感染等抗原性较差疾病中的 T 细胞反应性具有重要意义。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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