Notch signaling regulates function of human mucosal-associated invariant T (MAIT) cells.

IF 2.3 4区 医学 Q3 ALLERGY Asian Pacific journal of allergy and immunology Pub Date : 2024-03-01 DOI:10.12932/AP-010721-1174
Pimpayao Sodsai, Siriwan Klinchanhom, Nattiya Hirankarn, Rangsima Reantragoon, Tanapat Palaga
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Abstract

Background: Notch signaling plays an important role in the development of T lymphocytes and regulates their effector functions. The regulatory roles of Notch signaling on T cells have been intensely investigated, but whether it involves in effector functions of mucosal-associated invariant T (MAIT) cells has never been reported.

Objective: To elucidate the expression profiles of Notch receptors/ligands and to investigate their roles in human MAIT cell function.

Methods: Peripheral blood mononuclear cells (PBMCs) from health donors were stimulated with or without anti-CD3/ CD28-coupled beads, recombinant IL-12/IL-18 cytokines, riboflavin- or non-riboflavin-synthesizing bacterial cultured supernatant for 24 hours. The expression profiles of Notch receptors and ligands on MAIT cells were detected by flow cytometry. PBMCs were treated with a Notch signaling inhibitor, gamma secretase inhibitor (GSI), before stimulation to investigate the impact of interfering with Notch signaling on activation and function of MAIT cells.

Results: Resting MAIT cells predominantly expressed Notch2 receptor and the ligand, Jagged 2, on their surface. Upon stimulation, MAIT cells further upregulated Notch2 and also Notch1 with its cleaved form, indicating active Notch signaling. Cytokines and cytotoxic molecules which are secreted by activated MAIT cells, were suppressed by treatment with GSI. Moreover, both TCR-dependent MAIT cell activation by microbial-derived riboflavin intermediates and TCR-independent MAIT cell activation driven by IL-18 in synergy with IL-12, were blocked by GSI treatment.

Conclusions: Notch signaling is operating in MAIT cells and is involved in their activation both in a TCR-independent and -dependent manners.

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Notch信号调节人类粘膜相关不变T细胞(MAIT)的功能。
背景:Notch信号在T淋巴细胞的发育过程中发挥着重要作用,并调节着T淋巴细胞的效应功能。Notch信号对T细胞的调控作用已被深入研究,但它是否参与粘膜相关不变T细胞(MAIT)的效应功能却从未有过报道:阐明Notch受体/配体的表达谱,并研究它们在人类MAIT细胞功能中的作用:方法:用或不用抗 CD3/ CD28 偶联珠、重组 IL-12/IL-18 细胞因子、核黄素或非核黄素合成细菌培养上清刺激健康供体的外周血单核细胞(PBMC)24 小时。流式细胞术检测了 MAIT 细胞上 Notch 受体和配体的表达谱。在刺激前用Notch信号抑制剂--γ分泌酶抑制剂(GSI)处理PBMC,以研究干扰Notch信号对MAIT细胞活化和功能的影响:静息的MAIT细胞表面主要表达Notch2受体和配体Jagged 2。刺激后,MAIT细胞进一步上调Notch2和Notch1及其裂解形式,表明Notch信号活跃。活化的 MAIT 细胞分泌的细胞因子和细胞毒性分子受到 GSI 的抑制。此外,GSI 还能阻断微生物衍生核黄素中间产物对 TCR 依赖性 MAIT 细胞活化,以及 IL-18 与 IL-12 协同作用驱动的 TCR 依赖性 MAIT 细胞活化:结论:Notch 信号在 MAIT 细胞中起作用,并以独立于 TCR 和独立于 TCR 的方式参与其活化。
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来源期刊
CiteScore
12.80
自引率
0.00%
发文量
74
审稿时长
>12 weeks
期刊介绍: The Asian Pacific Journal of Allergy and Immunology (APJAI) is an online open access journal with the recent impact factor (2018) 1.747 APJAI published 4 times per annum (March, June, September, December). Four issues constitute one volume. APJAI publishes original research articles of basic science, clinical science and reviews on various aspects of allergy and immunology. This journal is an official journal of and published by the Allergy, Asthma and Immunology Association, Thailand. The scopes include mechanism, pathogenesis, host-pathogen interaction, host-environment interaction, allergic diseases, immune-mediated diseases, epidemiology, diagnosis, treatment and prevention, immunotherapy, and vaccine. All papers are published in English and are refereed to international standards.
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