Academic Journal
Metabolic alterations in cystic fibrosis lymphocyte memory accompany restoration of CFTR function.
| Τίτλος: | Metabolic alterations in cystic fibrosis lymphocyte memory accompany restoration of CFTR function. |
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| Συγγραφείς: | Saavedra MT; Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, United States., Rysavy NM; Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, United States., Poch KR; Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, United States., Caceres SM; Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, United States., Leach SM; Center for Genes, Environment and Health, National Jewish Health, Denver, CO, United States., Laborda C; Center for Genes, Environment and Health, National Jewish Health, Denver, CO, United States., Leti F; Center for Genes, Environment and Health, National Jewish Health, Denver, CO, United States., Walton KN; Center for Genes, Environment and Health, National Jewish Health, Denver, CO, United States., Danhorn T; Center for Genes, Environment and Health, National Jewish Health, Denver, CO, United States., Reisz JA; Department of Biochemistry and Molecular Genetics, University of CO Anschutz Medical Campus, Aurora, CO, United States., D'Alessandro A; Department of Biochemistry and Molecular Genetics, University of CO Anschutz Medical Campus, Aurora, CO, United States., Taylor-Cousar JL; Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, United States.; Division of Pediatric Pulmonary Medicine, National Jewish Health, Denver, CO, United States., Nick JA; Division of Pulmonary and Critical Care Medicine, National Jewish Health, Denver, CO, United States., Reinhardt RL; Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO, United States.; Department of Immunology and Microbiology, University of CO Anschutz Medical Campus, Aurora, CO, United States., Bratcher PE; Division of Pediatric Pulmonary Medicine, National Jewish Health, Denver, CO, United States., Vestal BE; Center for Genes, Environment and Health, National Jewish Health, Denver, CO, United States. |
| Πηγή: | American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2026 Oct 01; Vol. 74 (10), pp. 1389-1406. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: American Thoracic Society Country of Publication: England NLM ID: 8917225 Publication Model: Print Cited Medium: Internet ISSN: 1535-4989 (Electronic) Linking ISSN: 10441549 NLM ISO Abbreviation: Am J Respir Cell Mol Biol Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2000- : New York, NY : American Thoracic Society Original Publication: [New York, NY : The Association, [c1989- |
| Ιατρικοί όροι (MeSH): | Cystic Fibrosis Transmembrane Conductance Regulator*/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator*/genetics , Cystic Fibrosis*/immunology , Cystic Fibrosis*/metabolism , Cystic Fibrosis*/genetics , Cystic Fibrosis*/drug therapy , Lymphocytes*/metabolism , Immunologic Memory*, CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Humans ; Animals ; Adult ; Female ; Male ; Metabolomics ; Mice ; Transcriptome ; Mice, Inbred CFTR |
| Περίληψη: | Rationale: Elexacaftor/tezacaftor/ivacaftor (ETI) broadly improves outcomes in cystic fibrosis (CF). Cystic fibrosis transmembrane conductance regulator (CFTR) correction by ETI is incomplete, and patients with established disease continue to experience infection. We hypothesized that CFTR restoration by ETI would modify T-cell memory, providing a basis for improved infectious outcomes after treatment. Objectives: To evaluate ETI modification of lymphocyte signatures using transcriptomics and metabolomics in blood samples taken from adults with CF (awCF). Methods and Main Results: Circulating CD3+ T cells from awCF (n = 18) before and after ETI initiation were evaluated by cellular indexing of transcriptomes and epitopes by sequencing. Single-cell data profiled multiple T-cell populations, including naive, memory, and effector states, with the most extensive changes occurring in CD4+ T-cell populations. Simultaneous plasma metabolomic measurements were analyzed in association with CD4+ T-cell metabolic gene signatures. The relationships between clinical outcomes, cell-specific gene expression, and metabolomics were evaluated using generalized linear mixed models. The effect of reduced CFTR in lymphocytes was evaluated in vitro using CRISPR/Cas9-mediated CFTR knockdown in primary human lymphocyte cultures, as well as in splenocytes harvested from CFTR knockout mice. Conclusions: We reveal that altered metabolism occurs within the CD4+ T memory compartment following CFTR modulation, identifying multiple previously unrecognized changes in memory functions. Memory T-cell metabolic switches are highly related to a reduction in hospitalizations after treatment. Adaptive immune memory in awCF after modulator therapy is highly associated with improved outcomes from CF pulmonary infections, with variation seen in individuals experiencing lesser benefit after modulators. (© The Author(s) 2026. Published by Oxford University Press on behalf of the American Thoracic Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.) |
| Σχόλια: | Comment in: Am J Respir Cell Mol Biol. 2026 Oct 1;74(10):1325-1326. doi: 10.1093/ajrcmb/aanag060.. (PMID: 42113901) |
| Grant Information: | SAAVED19A0-PG Cystic Fibrosis Foundation |
| Contributed Indexing: | Keywords: cystic fibrosis; lymphocytes; metabolomics; transcriptomics |
| Substance Nomenclature: | 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) 0 (CFTR protein, human) |
| Entry Date(s): | Date Created: 20260512 Date Completed: 20260930 Latest Revision: 20260930 |
| Update Code: | 20260930 |
| DOI: | 10.1093/ajrcmb/aanag081 |
| PMID: | 42118592 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1535-4989 |
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| DOI: | 10.1093/ajrcmb/aanag081 |