Polygenic TB control and the sequence of innate/adaptive immune responses to infection: MHC-II alleles determine the size of the S100A8/9-producing neutrophil population

IF 4.9 3区 医学 Q2 IMMUNOLOGY Immunology Pub Date : 2024-07-14 DOI:10.1111/imm.13836
Nadezhda Logunova, Marina Kapina, Alexander Dyatlov, Tatiana Kondratieva, Elvira Rubakova, Konstantin Majorov, Elena Kondratieva, Irina Linge, Alexander Apt
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Abstract

Among several quantitative trait loci involved in tuberculosis (TB) control in mice, one was mapped within the chromosome 17 segment occupied by the H2 complex and another within the chromosome 3 segment comprising the S100A8/9 genes, which encode neutrophil inflammatory factor S100A8/9. Previously, we developed a panel of H2-congenic mouse strains differing by small segments of the major histocompatibility complex Class II (MHC-II) region from TB-susceptible H2j mice transferred onto the genetic background of the TB-resistant C57BL/6 (H2b) strain. Susceptible B6.I-9.3 mice differ from B6 progenitors by the alleles of their only classical MHC-II H2-Aβ gene. The goals of the present study were to: (i) comprehensively characterise the differences in TB-related phenotypes between mice of the two strains and (ii) decipher interactions between the H2-Aβ and S100A8/9 genes. Here, we describe the dynamics of TB-related phenotypes differentiating B6.I-9.3 and B6 mice (colony forming units counts, histopathology, lung immune cell infiltration and cytokine profiles). We show that disproportionally diminished CD4+ T-cell population, an enlarged S100A8/9-positive neutrophil population and higher S100A8/9 serum levels in B6.I-9.3 mice collectively form the ‘susceptible’ phenotype before infection. An increase in IL-17 and a decrease in intrferon-gamma production by CD4+ T-cells in these mice provide a mechanistic explanation of this phenotype. Using F2 segregation analysis, we show that the number of S100A8/9-producing neutrophils in lungs and spleens and the proportion of Th17 CD4+ T-cells in lungs are significantly lower in the presence of the MHC-II dominant ‘resistant’ b allele compared to the recessive ‘susceptible’ j/j genotype. This provides direct genetic evidence that MHC-II-regulated CD4+ T-cell landscapes determine neutrophil abundance before infection, an important pathogenic factor in TB immunity.

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多基因结核病控制和对感染的先天/适应性免疫反应序列:MHC-II等位基因决定了产生S100A8/9的中性粒细胞群体的规模。
在涉及小鼠结核病(TB)控制的几个数量性状位点中,有一个被绘制在由 H2 复合物占据的第 17 号染色体区段内,另一个被绘制在由编码中性粒细胞炎症因子 S100A8/9 的 S100A8/9 基因组成的第 3 号染色体区段内。此前,我们从结核病易感的 H2j 小鼠转入结核病抗性 C57BL/6(H2b)品系的遗传背景中,通过主要组织相容性复合体 II 类(MHC-II)区域的小片段,培育出了一组 H2 先天小鼠品系。易感 B6.I-9.3 小鼠与 B6 祖先的不同之处在于其唯一的经典 MHC-II H2-Aβ 基因的等位基因。本研究的目标是(i) 全面描述两个品系小鼠结核病相关表型的差异;(ii) 破译 H2-Aβ 和 S100A8/9 基因之间的相互作用。在这里,我们描述了 B6.I-9.3 和 B6 小鼠结核病相关表型(菌落形成单位计数、组织病理学、肺免疫细胞浸润和细胞因子图谱)的动态差异。我们发现,B6.I-9.3 小鼠的 CD4+ T 细胞数量不成比例地减少、S100A8/9 阳性的中性粒细胞数量增加以及 S100A8/9 血清水平升高共同构成了感染前的 "易感 "表型。这些小鼠体内 CD4+ T 细胞产生的 IL-17 增加和内干扰素-γ 减少为这种表型提供了机理解释。我们利用 F2 分离分析表明,与隐性 "易感 "j/j 基因型相比,MHC-II 显性 "抗性 "b 等位基因存在时,肺和脾中产生 S100A8/9 的中性粒细胞数量以及肺中 Th17 CD4+ T 细胞的比例显著降低。这提供了直接的遗传证据,表明 MHC-II 调节的 CD4+ T 细胞景观决定了感染前中性粒细胞的数量,而中性粒细胞是结核病免疫中的一个重要致病因素。
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来源期刊
Immunology
Immunology 医学-免疫学
CiteScore
11.90
自引率
1.60%
发文量
175
审稿时长
4-8 weeks
期刊介绍: Immunology is one of the longest-established immunology journals and is recognised as one of the leading journals in its field. We have global representation in authors, editors and reviewers. Immunology publishes papers describing original findings in all areas of cellular and molecular immunology. High-quality original articles describing mechanistic insights into fundamental aspects of the immune system are welcome. Topics of interest to the journal include: immune cell development, cancer immunology, systems immunology/omics and informatics, inflammation, immunometabolism, immunology of infection, microbiota and immunity, mucosal immunology, and neuroimmunology. The journal also publishes commissioned review articles on subjects of topical interest to immunologists, and commissions in-depth review series: themed sets of review articles which take a 360° view of select topics at the heart of immunological research.
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