Antigen specificity and cross-reactivity drive functionally diverse anti–Aspergillus fumigatus T cell responses in cystic fibrosis

BACKGROUND: The 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. METHODS: We used antigen-reactive T cell enrichment (ARTE) to investigate fungus-reactive Th cells in peripheral blood of pwCF and healthy controls. RESULTS: We 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. CONCLUSION: Our 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. FUNDING: German 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).