Klinikum Westbrandenburg, Campus Potsdam, Cystic Fibrosis Section, Potsdam, Germany.
Institute of Clinical Molecular Biology, Christian-Albrecht University of Kiel, Kiel, Germany.
J Clin Invest. 2023 Mar 1;133(5):e161593. doi: 10.1172/JCI161593.
BACKGROUNDThe fungus Aspergillus fumigatus causes a variety of clinical phenotypes in patients with cystic fibrosis (pwCF). Th cells orchestrate immune responses against fungi, but the types of A. fumigatus-specific Th cells in pwCF and their contribution to protective immunity or inflammation remain poorly characterized.METHODSWe used antigen-reactive T cell enrichment (ARTE) to investigate fungus-reactive Th cells in peripheral blood of pwCF and healthy controls.RESULTSWe show that clonally expanded, high-avidity A. fumigatus-specific effector Th cells, which were absent in healthy donors, developed in pwCF. Individual patients were characterized by distinct Th1-, Th2-, or Th17-dominated responses that remained stable over several years. These different Th subsets target different A. fumigatus proteins, indicating that differential antigen uptake and presentation directs Th cell subset development. Patients with allergic bronchopulmonary aspergillosis (ABPA) are characterized by high frequencies of Th2 cells that cross-recognize various filamentous fungi.CONCLUSIONOur data highlight the development of heterogenous Th responses targeting different protein fractions of a single fungal pathogen and identify the development of multispecies cross-reactive Th2 cells as a potential risk factor for ABPA.FUNDINGGerman Research Foundation (DFG), under Germany's Excellence Strategy (EXC 2167-390884018 "Precision Medicine in Chronic Inflammation" and EXC 2051-390713860 "Balance of the Microverse"); Oskar Helene Heim Stiftung; Christiane Herzog Stiftung; Mukoviszidose Institut gGmb; German Cystic Fibrosis Association Mukoviszidose e.V; German Federal Ministry of Education and Science (BMBF) InfectControl 2020 Projects AnDiPath (BMBF 03ZZ0838A+B).
烟曲霉可引起囊性纤维化（pwCF）患者的多种临床表型。辅助性 T 细胞（Th 细胞）可协调机体对真菌的免疫反应，但 pwCF 患者中针对烟曲霉的特异性 Th 细胞类型及其对保护性免疫或炎症的贡献仍知之甚少。
我们使用抗原反应性 T 细胞富集（ARTE）来研究 pwCF 患者和健康对照者外周血中的真菌反应性 Th 细胞。
我们发现，在健康供体中不存在的克隆扩增、高亲和力的烟曲霉特异性效应性 Th 细胞在 pwCF 中发育。每个患者的特征是存在以 Th1、Th2 或 Th17 为主的反应，这些反应在数年内保持稳定。这些不同的 Th 亚群针对不同的烟曲霉蛋白，表明不同的抗原摄取和呈递可指导 Th 细胞亚群的发育。过敏性支气管曲霉病（ABPA）患者的特征是高频率的 Th2 细胞，这些细胞可交叉识别各种丝状真菌。
我们的数据强调了针对单一真菌病原体的不同蛋白片段的异质性 Th 反应的发展，并确定了多物种交叉反应性 Th2 细胞的发展是 ABPA 的一个潜在危险因素。
德国研究基金会（DFG），在德国卓越战略（EXC 2167-390884018“慢性炎症中的精准医学”和 EXC 2051-390713860“微观世界的平衡”）下；Oskar Helene Heim 基金会；Christiane Herzog 基金会；囊性纤维化研究所；德国囊性纤维化协会；德国联邦教育与研究部（BMBF）InfectControl 2020 项目 AnDiPath（BMBF 03ZZ0838A+B）。
