Beyond a binary view of cystic fibrosis: systemic immunity and inflammation across the spectrum of CFTR dysfunction
Cystic fibrosis is traditionally framed as a dichotomy between affected individuals and clinically unaffected carriers, yet the systemic immune consequences across the spectrum of CFTR functionality remain incompletely defined. The advent of highly effective CFTR modulators now provides a unique momentum to examine whether partial restoration of CFTR function can influence systemic immunity. Using multimodal immune profiling, we constructed a single-cell atlas of circulating immune cells in people with cystic fibrosis (pwCF), healthy F508del carriers and non-carriers. In pwCF, systemic immunity was markedly altered following in vivo CFTR modulation with elexacaftor-tezacaftor-ivacaftor, with broad reductions in pro-inflammatory cytokines linked to improved clinical outcomes. Notably, healthy F508del carriers exhibited a CF-like immune signature characterised by low-grade systemic inflammation, including elevated IL-6, reduced mucosal-associated invariant T cells, and inflammatory monocyte features overlapping with pwCF. Together, these findings show that CFTR-related immune dysregulation extends beyond classical cystic fibrosis, challenging a strict dichotomy between health and disease.