CD4-mediated immunity shapes neutrophil-driven tuberculous pathology.
CD4-mediated immunity shapes neutrophil-driven tuberculous pathology.
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CD4 介导的免疫塑造了中性粒细胞驱动的结核病病理。
DOI：
10.1101/2024.04.12.589315
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Urdahl,K
中科院分区：
文献类型：
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作者：
Gern,BenjaminH;Klas,JosephaM;Foster,KimberlyA;Cohen,SaraB;Plumlee,CourtneyR;Duffy,FergalJ;Neal,MaxwellL;Halima,Mehnaz;Gustin,AndrewT;Diercks,AlanH;Aderem,Alan;GaleJr,Michael;Aitchison,JohnD;Gerner,MichaelY;Urdahl,K
结核分枝杆菌（Mtb）感染导致高度不均匀的病变，从伴有中央坏死的肉芽肿到主要由肺泡炎组成的肉芽肿。虽然在人类死后研究中肺泡炎与先前免疫有关，但这些不同病理结果的驱动因素尚不清楚。在这里，我们发现这些不同的病变结构可以在C3HeB/FeJ小鼠中建模，并受到先前免疫的调节。通过定量成像、scRNAseq和流式细胞术，我们证明在没有事先免疫的情况下，结核分枝杆菌感染会引起中性粒细胞募集失调和坏死性肉芽肿。相反，先前免疫诱导T细胞的快速募集和激活、局部巨噬细胞激活和晚期中性粒细胞反应的减弱。不同感染阶段的耗竭研究表明，慢性阶段的早期坏死起始和坏死增殖需要中性粒细胞，而早期CD4 T细胞反应阻止中性粒细胞前传回路和坏死。总之，这些研究揭示了结核病病变结构和发病机制的基本决定因素，这对预防或治疗结核病的新策略具有重要意义。
Pulmonary Mycobacterium tuberculosis (Mtb) infection results in highly heterogeneous lesions ranging from granulomas with central necrosis to those primarily comprised of alveolitis. While alveolitis has been associated with prior immunity in human post-mortem studies, the drivers of these distinct pathologic outcomes are poorly understood. Here, we show that these divergent lesion structures can be modeled in C3HeB/FeJ mice and are regulated by prior immunity. Using quantitative imaging, scRNAseq, and flow cytometry, we demonstrate that Mtb infection in the absence of prior immunity elicits dysregulated neutrophil recruitment and necrotic granulomas. In contrast, prior immunity induces rapid recruitment and activation of T cells, local macrophage activation, and diminished late neutrophil responses. Depletion studies at distinct infection stages demonstrated that neutrophils are required for early necrosis initiation and necrosis propagation at chronic stages, whereas early CD4 T cell responses prevent neutrophil feedforward circuits and necrosis. Together, these studies reveal fundamental determinants of tuberculosis lesion structure and pathogenesis, which have important implications for new strategies to prevent or treat tuberculosis.