Infectious Disease and Microbiome Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Disease Systems Immunology, Department of Biotechnology and Biomedicine, Section for Protein Science and Biotherapeutics, Technical University of Denmark, 2800 Kongens Lyngby, Denmark.
Infectious Disease and Microbiome Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Immunity. 2022 Oct 11;55(10):1909-1923.e6. doi: 10.1016/j.immuni.2022.08.016. Epub 2022 Sep 16.
Reciprocal interactions between host T helper cells and gut microbiota enforce local immunological tolerance and modulate extra-intestinal immunity. However, our understanding of antigen-specific tolerance to the microbiome is limited. Here, we developed a systematic approach to predict HLA class-II-specific epitopes using the humanized bacteria-originated T cell antigen (hBOTA) algorithm. We identified a diverse set of microbiome epitopes spanning all major taxa that are compatible with presentation by multiple HLA-II alleles. In particular, we uncovered an immunodominant epitope from the TonB-dependent receptor SusC that was universally recognized and ubiquitous among Bacteroidales. In healthy human subjects, SusC-reactive T cell responses were characterized by IL-10-dominant cytokine profiles, whereas in patients with active Crohn's disease, responses were associated with elevated IL-17A. Our results highlight the potential of targeted antigen discovery within the microbiome to reveal principles of tolerance and functional transitions during inflammation.
宿主辅助性 T 细胞和肠道微生物群之间的相互作用强制局部免疫耐受，并调节肠道外免疫。然而，我们对微生物组的抗原特异性耐受的理解是有限的。在这里，我们使用人类起源的 T 细胞抗原 (hBOTA) 算法开发了一种预测 HLA Ⅱ类特异性表位的系统方法。我们确定了一组多样化的微生物组表位，涵盖了所有主要类群，与多种 HLA-II 等位基因的呈递兼容。特别是，我们从 TonB 依赖性受体 SusC 中发现了一个免疫优势表位，该表位在拟杆菌目中普遍存在且无处不在。在健康的人类受试者中，SusC 反应性 T 细胞反应的特征是白细胞介素 10 占主导地位的细胞因子谱，而在活动性克罗恩病患者中，反应与白细胞介素 17A 升高相关。我们的结果强调了在微生物组中进行靶向抗原发现的潜力，以揭示在炎症过程中耐受和功能转换的原则。
