Type 3 innate lymphoid cells dominate the ILC compartment in endstage lung disease.

Mucosal innate lymphoid cells (ILCs) act as cytokine producers in first line defense but also as contributors to chronic inflammation. We have previously shown that ILCs belong to those non-conventional lymphocytes promoting an IL-17A-rich tissue environment in endstage lung tissue. Here, we provide an in-depth characterization of ILCs in lung and lung-draining lymph nodes (LNs) from patients with three endstage lung diseases, i.e. cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD)/emphysema, and pulmonary fibrosis, which reveals critical differences to healthy lung tissue. Our analyses show that type 3 ILCs dominate the ILC compartment in lungs and LNs from these three endstage lung disease entities, where they contribute to the pro-inflammatory cytokine milieu in the tissue, whereas type 1 ILCs constitute the major ILC population in healthy lung tissue. In contrast to the endstage situation, in the peripheral blood (PB) of clinically stable CF patients, we find type 2 ILCs at increased frequencies compared to healthy controls. In CF patients receiving the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI), these differences in PB ILC composition are sustained for up to 24 months, in spite of significant reductions of systemic inflammation, which accompany strong improvements in lung function. These findings suggest that the local and systemic ILCs compartments reflect unique immunological aspects of chronic lung disease which appear challenging to address by disease-modifying treatment.