# Systemic and airway T cell dynamics with influenza-specific immune recovery by cystic fibrosis elexacaftor/tezacaftor/ivacaftor therapy

## TL;DR

This study shows that ETI therapy in cystic fibrosis patients improves immune function in the lungs and blood, leading to better health outcomes.

## Contribution

The study reveals novel immunological effects of ETI therapy on T cell dynamics in both airways and systemic circulation in cystic fibrosis.

## Key findings

- ETI treatment increases T cell abundance in sputum and improves lung function.
- Peripheral blood shows expanded effector-memory CD8 and CD4 T cells during ETI.
- Influenza-specific T cell responses recover during ETI therapy.

## Abstract

Therapy with elexacaftor/tezacaftor/ivacaftor (ETI) works to improve the functionality of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein and has revolutionized CF treatment. However, the implications of ETI for airway barrier and systemic T cell immunobiology remain relatively little studied.

Here, we investigated the immunological effects of ETI at systemic and local pulmonary levels, using paired peripheral blood and sputum sampling, in relation to key clinical parameters. Samples were taken longitudinally at baseline (n = 27), and at three (n = 24) and 12 months (n = 19) of treatment and subjected to analysis by advanced flow cytometry, T cell assays, and plasma proteomics.

Before ETI treatment initiation, immune cell composition in the sputum closely reflected the plasma inflammatory proteome. T cell abundance in sputum correlated inversely with multiple plasma factors, including IL-17A, IL-8, HGF and TGFα, and with lower sweat chloride concentrations. Chronic microbial infection was associated with low abundance of CD4 T cells and mucosa-associated invariant T (MAIT) cells in sputum samples collected at baseline. During ETI treatment, T cells with lung resident characteristics including MAIT cells increased in sputum, accompanied by improved lung function and reduced systemic inflammation. In peripheral blood, the effector-memory CD8 and CD4 T cell pool expanded and the magnitude and quality of T cell responses to Influenza A virus recovered during ETI.

These findings indicate that ETI treatment promotes immunological remodelling in both airways and circulation, correlating with favorable changes in clinically relevant parameters, and a shift towards healthy immune regulation in the lung and improved adaptive T cell responses in circulation.

The online version contains supplementary material available at 10.1186/s12931-026-03521-9.