Primary Supervisor: Prof. A. Santoni, Istituto Pasteur-Rome, Italy
Title: How innate lymphoid cells modulate inflammation by targeting STAT4
Collaborators: Dr. M. Kikkert, LUMC, Leiden, The Netherlands; Dr. K. Pardali, AstraZeneca, Gothenburg, Sweden
Early Stage Researcher, TBA (add once Early Stage Researcher list final)
Innate lymphoid cells (ILCs) comprise specialized cytokine producer cells, which ensure barrier integrity and provide protection against bacterial and viral infections. Despite their recognized similarity with T cells, ILCs are endowed with distinctive features, including lack of antigen requirement for activation and an emerging role in regulation of metabolic homeostasis. However, the molecular mechanisms underlying ILC effector functions and their specific role in the context of an intact T cell response are still undisclosed. Members of the Signal Transducer and Activator of Transcription (STAT) family are important mediators for ILC homeostasis and effector functions. Due to the relevance of STAT4 signaling during viral infection and inflammation, targeting this pathway represents an attractive therapeutic strategy for several diseases. Preliminary results from our laboratory show a broad expression of STAT4 in ILCs expressing natural cytotoxicity receptors (NCR+ILCs), and evidence for a role of STAT4 expression by innate cells during inflammation. We hypothesize that STAT4 regulates transcriptomic modules in ILCs that are critically important in the outcome of infections, inflammation-driven diseases, and metabolic homeostasis.
ESR10 will generate a novel mouse strain with selective STAT4 deletion in NCR+ILCs. These mice will be tested for ability to clear influenza virus A (IAV) infection. Also in the inflammation setting of EAE colitis (induced by administration of dextran sulfate sodium in the drinking water) or colitis-induced colorectal cancer, ILC populations will be evaluated by polychromatic flow cytometry. Cutting-edge next-generation sequencing technologies will be used to define STAT4-dependent transcriptional modules in ILCs. Bioinformatics analyses will be performed to unravel novel protective and/or pathogenic pathways in ILCs. In collaboration with Astra Zeneca, ESR10 will evaluate the role of STAT4 signaling in human ILCs. Taking advantage of the local expertise on manipulation of human ILCs, the STAT4 gene will be targeted using CRISPr/Cas9 system and ILC functions and gene expression profiles will be assessed. In collaboration with Dr. Kikkert at LUMC, ESR10 will evaluate the relevance of ILCs and STAT4 signaling in the context of coronavirus infections (MHV and/or MERS-CoV) using the STAT4 conditional knock-out mice made in the project.