Mapping the T cell repertoire to a complex gut bacterial community.
Mapping the T cell repertoire to a complex gut bacterial community.
复制标题
将 T 细胞库映射到复杂的肠道细菌群落。
DOI：
10.1038/s41586-023-06431-8
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发表时间：
2023
期刊：
影响因子：
64.8
通讯作者：
Balskus,
中科院分区：
文献类型：
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作者：
Nagashima,Kazuki;Zhao,Aishan;Atabakhsh,Katayoon;Bae,Minwoo;Blum,JamieE;Weakley,Allison;Jain,Sunit;Meng,Xiandong;Cheng,AliceG;Wang,Min;Higginbottom,Steven;Dimas,Alex;Murugkar,Pallavi;Sattely,ElizabethS;Moon,JamesJ;Balskus,
来自微生物组的某些细菌菌株诱导一种有效的抗原特异性T细胞反应，，，-。然而，微生物组诱导的T细胞的特异性尚未在整个肠道群落的菌株水平上进行探索。在这里，我们用复杂的定义群落（大约100种细菌菌株）定植无菌小鼠，并描述T细胞对每种菌株的反应。这种反应模式表明，肠道中的许多T细胞可以识别来自社区的几种细菌菌株。我们利用92个T细胞受体（TCR）克隆型构建了T细胞杂交瘤；通过筛选群落中针对每种杂交瘤的每种菌株，我们发现几乎所有细菌特异性TCR都表现出一对多的TCR-菌株关系，包括13种丰富的TCR克隆型，每种克隆型识别18种厚壁菌门。通过筛选三个汇集的细菌基因组文库，我们发现这13个克隆型共享一个目标：来自atp结合盒运输系统的保守底物结合蛋白。外周调节性T细胞和T辅助17细胞对该蛋白表位的特异性在社区定植和特异性无病原体小鼠中大量存在。我们的研究表明，T细胞对共生体的识别主要集中在广泛保守的、高度表达的细胞表面抗原上，这为合理改变或重定向殖民者特异性免疫反应的新治疗策略打开了大门。
Certain bacterial strains from the microbiome induce a potent, antigen-specific T cell response, , , –. However, the specificity of microbiome-induced T cells has not been explored at the strain level across the gut community. Here, we colonize germ-free mice with complex defined communities (roughly 100 bacterial strains) and profile T cell responses to each strain. The pattern of responses suggests that many T cells in the gut repertoire recognize several bacterial strains from the community. We constructed T cell hybridomas from 92 T cell receptor (TCR) clonotypes; by screening every strain in the community against each hybridoma, we find that nearly all the bacteria-specific TCRs show a one-to-many TCR-to-strain relationship, including 13 abundant TCR clonotypes that each recognize 18 Firmicutes. By screening three pooled bacterial genomic libraries, we discover that these 13 clonotypes share a single target: a conserved substrate-binding protein from an ATP-binding cassette transport system. Peripheral regulatory T cells and T helper 17 cells specific for an epitope from this protein are abundant in community-colonized and specific pathogen-free mice. Our work reveals that T cell recognition of commensals is focused on widely conserved, highly expressed cell-surface antigens, opening the door to new therapeutic strategies in which colonist-specific immune responses are rationally altered or redirected.