Saavedra et al. find that restoring CFTR with ETI shifts CD4+ memory T cells in CF toward oxidative metabolism, with metabolic gene changes linked to FEV1 improvement and fewer hospitalizations
Saavedra and colleagues used CITE-seq to profile circulating CD3+ T cells from 18 adults with cystic fibrosis before and after starting elexacaftor-tezacaftor-ivacaftor (ETI), finding CFTR modulation induces transcriptional reprogramming most pronounced in CD4+ memory T cells (upregulation of PNP and MT1X, enrichment of mitochondrial metabolism and oxidative phosphorylation pathways, and decline in chromatin remodeling and inflammatory activation genes), while Seahorse metabolic flux analysis, splenocytes from CFTR F508del homozygous mice, and CRISPR-Cas9 knockdown of CFTR in primary human lymphocytes all show reduced oxygen consumption, glycolytic capacity, and ATP production in CF lymphocytes, and changes in CD4+ memory T cell gene expression correlate with FEV1 improvement and reduced h