Cystic fibrosis and the role of CFTR in circulating immune cells: a human single-cell atlas

The impact of CFTR dysfunction on airway inflammation in people living with cystic fibrosis (PwCF) has been clearly established. However, the effect of CFTR dysfunction on circulating immune cells remains poorly understood. We aimed to establish a single-cell atlas in CF, mapping the dynamics of circulating immune cells when CFTR functionality is enhanced in vivo. We assessed the impact of CFTR dysfunction at the single-cell level using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq). We profiled peripheral blood mononuclear cells (PBMCs) from 8 PwCF homozygous for <italic>F508del</italic>, 4 healthy <italic>F508del</italic> carriers, and 4 non-carriers of CFTR mutations. PwCF were longitudinally sampled in steady state, before and during treatment with CFTR modulators. Our single-cell atlas reveals that in vivo CFTR modulation changes the dynamics of circulating immune cells. Through the application of CITE-seq of 263,543 PBMCs, we demonstrate shifts in transcriptome, surface markers, and intercellular communication. Using healthy <italic>F508del</italic> carriers and non-carriers as controls, we outline these changes against differing levels of CFTR functionality. <fig><object-id>erj;64/suppl_68/OA2902/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig> We present the first single-cell atlas of PBMCs in PwCF before and during treatment with CFTR modulation, and in healthy controls genotyped as either <italic>F508del</italic> carriers or non-carriers. This unbiased approach enables us to further elucidate the role of CFTR in our immune system.