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

Carsten Schwarz, Patience Eschenhagen, Henrijette Schmidt, Thordis Hohnstein, Christina Iwert, Claudia Grehn, Jobst Roehmel, Eva Steinke, Mirjam Stahl, Laura Lozza, Ekaterina Tikhonova, Elisa Rosati, Ulrik Stervbo, Nina Babel, Jochen G Mainz, Hilmar Wisplinghoff, Frank Ebel, Lei-Jie Jia, Matthew G Blango, Peter Hortschansky, Sascha Brunke, Bernhard Hube, Axel A Brakhage, Olaf Kniemeyer, Alexander Scheffold, Petra Bacher
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The journal of clinical investigation
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<h4>Background</h4>The fungus Aspergillus fumigatus causes a variety of clinical phenotypes in patients with cystic fibrosis (pwCF). T-helper (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.<h4>Methods</h4>We used antigen-reactive T cell enrichment (ARTE) to investigate fungus-reactive Th cells in peripheral blood of pwCF and healthy controls.<h4>Results</h4>We show that clonally expanded, high-avidity A. fumigatus-specific effector Th-cells develop in pwCF, which are absent in healthy donors. Individual patients were characterized by distinct Th1, Th2, or Th17 dominated responses that remained stable over 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.<h4>Conclusion</h4>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.<h4>Funding</h4>This research was supported by grants from the German Research Foundation (DFG) under Germany's Excellence Strategy - EXC 2167-390884018 "Precision Medicine in Chronic Inflammation", EXC 2051-390713860 "Balance of the Microverse"; the Oskar Helene Heim Stiftung; the Christiane Herzog Stiftung, Stuttgart, Germany; the Mukoviszidose Institut gGmbH, Bonn, the research and development arm of the German Cystic Fibrosis Association Mukoviszidose e.V; the German Federal Ministry of Education and Science (BMBF) InfectControl 2020 Projects AnDiPath, BMBF 03ZZ0838A+B.