Proliferative activity of antigen-specific CD154+ T cells against bacterial and fungal respiratory pathogens in cystic fibrosis decreases after initiation of highly effective CFTR modulator therapy

Patience N Eschenhagen; Petra Bacher; Claudia Grehn; Jochen G Mainz; Alexander Scheffold; Carsten Schwarz

doi:10.3389/fphar.2023.1180826

Proliferative activity of antigen-specific CD154+ T cells against bacterial and fungal respiratory pathogens in cystic fibrosis decreases after initiation of highly effective CFTR modulator therapy

Front Pharmacol. 2023 Jun 20:14:1180826. doi: 10.3389/fphar.2023.1180826. eCollection 2023.

Authors

Patience N Eschenhagen^{1

2

3}, Petra Bacher^{4

5}, Claudia Grehn⁶, Jochen G Mainz^{7

8}, Alexander Scheffold⁴, Carsten Schwarz^{1

2

3}

Affiliations

¹ Cystic Fibrosis Section, Klinikum Westbrandenburg, Campus Potsdam, Potsdam, Germany.
² HMU Health and Medical University, Potsdam, Germany.
³ Department of Pediatric Pneumology, Immunology and Intensive Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.
⁴ Institute of Clinical Molecular Biology, Christian-Albrecht-University of Kiel, Kiel, Germany.
⁵ Institute of Immunology, Christian-Albrecht-University of Kiel and UKSH Schleswig-Holstein, Kiel, Germany.
⁶ Berlin Institute of Health at Charité Universitätsmedizin, Berlin, Germany.
⁷ Cystic Fibrosis Center, Brandenburg Medical School (MHB) University, Brandenburg, Germany.
⁸ Faculty of Health Sciences Joint Faculty of the Brandenburg University of Technology Cottbus-Senftenberg, The Brandenburg Medical School Theodor Fontane and the University of Potsdam, Potsdam, Germany.

Abstract

Background: Together with impaired mucociliary clearance, lung disease in cystic fibrosis (CF) is driven by dysregulation of innate and adaptive immunity caused by dysfunctional CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), leading to airway infection and hyperinflamma-tion. The highly effective CFTR modulator therapy (HEMT) elexacaftor/tezacaftor/ivacaftor (ETI) generates substantial improvements in clinical outcomes of people with CF (pwCF) by restoration of CFTR activity. Aberrant immune responses of lymphocytes due to CFTR dysfunction has been described in the past, but not the effects of CFTR restoration by HEMT on these cells. We aimed to examine the effect of ETI on the proliferative activity of antigen-specific CD154 (+) T cells against bacterial and fungal species relevant in CF and on total IgG and IgE as markers of B cell adaptive immunity. Methods: We performed ex vivo analyses of Ki-67 expression in antigen-specific CD154 (+) T cells against Pseudomonas aeruginosa, Staphylococcus aureus, Aspergillus fumigatus, Scedosporium apiospermum and Candida albicans from 21 pwCF by cytometric assay based on antigen-reactive T cell enrichment (ARTE), and analysis of total serum IgE and IgG before and after initiation of ETI. Results: Mean Ki-67 expression in antigen-specific CD154 (+) T cells against P. aeruginosa, A. fumigatus, S. apiospermum and C. albicans, but not S. aureus, mean total serum IgG and mean total serum IgE decreased significantly after initiation of ETI. No correlation was found to change in sputum microbiology of the examined pathogens. Mean BMI and FEV1 increased significantly. Conclusion: HEMT is associated with decreased antigen-specific CD154 (+) T cell proliferation activity in our cohort, independent of findings in sputum microbiology of the examined pathogens. Together with the observed clinical improvement and the decrease in total IgE and IgG, this indicates effects due to CFTR restoration on CD154 (+) T cells by ETI and a reduction of B cell activation with subsequent lower immunoglobulin synthesis under HEMT therapy. These results endorse earlier evidence of CFTR dysfunction in T and B cells leading directly to aberrant immune responses with hyperinflammation.

Keywords: Aspergillus fumigatus; Ki-67; Pseudomonas aeruginosa; antigen-specific T cells; cystic fibrosis; highly effective modulator therapy; total IgE; total IgG.