Antigen specificity and cross-reactivity drive functionally diverse anti–Aspergillus fumigatus T cell responses in cystic fibrosis
Carsten Schwarz, … , Alexander Scheffold, Petra Bacher
Carsten Schwarz, … , Alexander Scheffold, Petra Bacher
Published January 26, 2023
Citation Information: J Clin Invest. 2023;133(5):e161593. https://doi.org/10.1172/JCI161593.
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Clinical Research and Public Health Immunology Pulmonology

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

Abstract

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).

Authors

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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Figure 3

Different T cell reactivity pattern against A. fumigatus in pwCF.

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Different T cell reactivity pattern against A. fumigatus in pwCF. (A) Ex...
(A) Ex vivo cytokine production of A. fumigatus–reactive CD154+ Tmem cells from healthy donors (IFN-γ, n = 158; IL-17A, n = 158; IL-4, n = 134; IL-10, n = 87) and pwCF (n = 200). (B) Representative dot plots for ex vivo cytokine staining of A. fumigatus–stimulated cells following ARTE. The percentage of cytokine-producing cells within CD154+ Tmem cells is indicated. (C) Direct comparison of A. fumigatus–reactive cytokine production for healthy donors (n = 134) and pwCF (n = 200). Cut-off values for cytokine-producing cells within CD154+ Tmem cells were determined by ROC analysis (see Supplemental Figure 2). Donors whose cell percentages exceeded the cut-off are color coded (yellow: IFN-γ ≥29%; light green: IL-17A ≥6.1%; light blue: IL-4lo ≥6.9%; dark blue: IL-4hi ≥12.9%. (D) Frequencies of A. fumigatus–reactive Tmem cells, as well as total and specific IgE levels for pwCF within the different A. fumigatus–specific T cell reactivity groups. (E) Representative plots depicting the stability of the different A. fumigatus–specific cytokine reactivity patterns. A. fumigatus–reactive T cells of pwCF were monitored at least 4 times over a period of up to 4 years. Relative expression of IFN-γ, IL-17A, and IL-4 within the CD154+ Tmem population is shown. (F) Distribution of the different A. fumigatus–specific cytokine reactivity patterns for healthy donors and pwCF. The percentages of donors in each group are indicated. (G) Incidence of ABPA in the different A. fumigatus–specific T cell reactivity groups. The percentages indicate patients with acute ABPA, a history of ABPA, or who never had ABPA at the time the measurement was done. (H) Heatmap depicting the correlation of the different A. fumigatus–reactive T cell groups with clinical parameters. Values were z score normalized for each parameter and are plotted as the mean value for each T cell reactivity group. Each symbol in A, C, and D represents 1 donor; horizontal lines indicate the mean in A. Truncated violin plots with quartiles and range are shown in D. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-tailed Mann-Whitney U test (A) and Kruskal-Wallis test with Dunn’s post hoc test (D).