Phenotype and function of innate lymphoid cells in cystic fibrosis lung disease

• Applicant: Professorin Dr. Anna-Maria Dittrich
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 428163432

Cystic fibrosis (CF) is the most common autosomal recessive progressive lung disease in Northern and Central Europe. CF lung disease is characterized by a vicious cycle of inflammation and infection that leads to progressive destruction of lung tissue. This destruction of lung tissue by a neutrophilic inflammation determines the course of the disease and still shortens the life expectancy of patients with cystic fibrosis. Anti-inflammatory approaches are therefore a central concern of patient-oriented CF research, especially as well-known anti-inflammatory drugs, such as steroids, have so far failed to show sufficient anti-inflammatory effects on CF lung disease.ILCs contribute to the early immune defense of a variety of bacterial and fungal infections characteristic of the acute and chronic respiratory tract infections in CF lung disease, e.g. Pseudomonas aeruginosa or Aspergillus fumigatus. As tissue-resident lymphocytes located beneath the mucosal surface, innate lymphoid cells (ILCs) respond to epithelial signals that control the expansion and differentiation of ILCs. ILCs in turn contribute to immune defense mechanisms by controlling the expansion and differentiation of other effector cells of the immune system and possibly support the formation of immunological memory. ILCs mediate these effects by cytokine secretion and surface molecules, such as costimulatory molecules, MHCII and checkpoint inhibitor molecules. Our preliminary data in CF lung tissue and CF-like mouse models suggest that ILCs contribute to the development of neutrophilic inflammation in CF lung disease. However, it has not yet been clarified which ILC-derived signals underlie neutrophilic lung inflammation in CF lung disease. Furthermore, the role of infectious and/or allergic stimuli for the contribution of ILCs to CF lung disease has not been addressed.The dependence of ILC effector function on secreted cytokines and surface molecules suggests that appropriate approaches to modulate ILC-associated cytokines and / or surface molecules may be a promising approach to target the neutrophil inflammatory response to influence CF lung disease. For this proposal, we therefore aim to identify ILC-associated mediators of CF lung disease by a comprehensive characterization of the repertoire of cytokines and surface molecules and other signaling pathways of CF lung tissue and CF-like mouse models. In a second step, we propose to assess the functional relevance of these mediators in appropriate mouse models and cell culture systems in order to provide a basis for further pre-clinical and clinical studies aimed at modulating the ILC-mediated inflammatory response in CF lung disease.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1937: Innate Lymphoid Cells