Type I IFN signaling in the absence of IRGM1 promotes M. tuberculosis replication in immune cells by suppressing T cell responses

IF 7.9 2区 医学 Q1 IMMUNOLOGY Mucosal Immunology Pub Date : 2024-10-01 DOI:10.1016/j.mucimm.2024.07.002
Sumanta K. Naik, Michael E. McNehlan, Yassin Mreyoud, Rachel L. Kinsella, Asya Smirnov, Chanchal Sur Chowdhury, Samuel R. McKee, Neha Dubey, Reilly Woodson, Darren Kreamalmeyer, Christina L. Stallings
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Abstract

Polymorphisms in the IRGM gene are associated with susceptibility to tuberculosis in humans. A murine ortholog of Irgm, Irgm1, is also essential for controlling Mycobacterium tuberculosis (Mtb) infection in mice. Multiple processes have been associated with IRGM1 activity that could impact the host response to Mtb infection, including roles in autophagy-mediated pathogen clearance and expansion of activated T cells. However, what IRGM1-mediated pathway is necessary to control Mtb infection in vivo and the mechanistic basis for this control remains unknown. We dissected the contribution of IRGM1 to immune control of Mtb pathogenesis in vivo and found that Irgm1 deletion leads to higher levels of IRGM3-dependent type I interferon signaling. The increased type I interferon signaling precludes T cell expansion during Mtb infection. The absence of Mtb-specific T cell expansion in Irgm1−/− mice results in uncontrolled Mtb infection in neutrophils and alveolar macrophages, which directly contributes to susceptibility to infection. Together, our studies reveal that IRGM1 is required to promote T cell-mediated control of Mtb infection in neutrophils, which is essential for the survival of Mtb-infected mice. These studies also uncover new ways type I interferon signaling can impact TH1 immune responses.
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在 IRGM1 缺失的情况下,I 型 IFN 信号通过抑制 T 细胞反应促进结核杆菌在免疫细胞中的复制。
IRGM基因的多态性与人类对结核病的易感性有关。Irgm的小鼠直向同源物Irgm1也是控制小鼠结核分枝杆菌(Mtb)感染的关键。与IRGM1活性相关的多个过程可能会影响宿主对Mtb感染的反应,包括在自噬介导的病原体清除和活化T细胞扩增中的作用。然而,IRGM1 介导的哪种途径是控制体内 Mtb 感染所必需的,以及这种控制的机理基础仍然未知。我们剖析了IRGM1对体内Mtb发病的免疫控制的贡献,发现Irgm1缺失会导致IRGM3依赖的I型干扰素信号水平升高。I型干扰素信号的增加阻止了T细胞在Mtb感染期间的扩增。Irgm1-/-小鼠缺乏Mtb特异性T细胞扩增,导致中性粒细胞和肺泡巨噬细胞中的Mtb感染失控,从而直接导致感染易感性。总之,我们的研究揭示了IRGM1是促进T细胞介导的中性粒细胞Mtb感染控制所必需的,这对Mtb感染小鼠的存活至关重要。这些研究还发现了 I 型干扰素信号转导影响 TH1 免疫反应的新途径。
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来源期刊
Mucosal Immunology
Mucosal Immunology 医学-免疫学
CiteScore
16.60
自引率
3.80%
发文量
100
审稿时长
12 days
期刊介绍: Mucosal Immunology, the official publication of the Society of Mucosal Immunology (SMI), serves as a forum for both basic and clinical scientists to discuss immunity and inflammation involving mucosal tissues. It covers gastrointestinal, pulmonary, nasopharyngeal, oral, ocular, and genitourinary immunology through original research articles, scholarly reviews, commentaries, editorials, and letters. The journal gives equal consideration to basic, translational, and clinical studies and also serves as a primary communication channel for the SMI governing board and its members, featuring society news, meeting announcements, policy discussions, and job/training opportunities advertisements.
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