Understanding the Mechanisms Underlying the Development and Function of Tissue-Resident Immune Niches

• Applicant: Professorin Dr. Mirka Uhlirova
• Subject Area: Developmental Biology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 573567388

Innate immune cells of the myeloid lineage are essential for the development and survival of all metazoans. Their differentiation and function are tightly linked to specialized compartments known as niches. Hematopoietic and tissue-specific niches provide microenvironments that support self-renewal, progenitor maintenance, and immune cell differentiation in response to tissue and organismal needs. Crosstalk within these niches depends on biochemical and mechanical signals involving secreted factors, cell-matrix contacts, and cell-cell interactions. Disruptions in niche integrity can lead to tissue dysfunction and disease. However, our understanding of the complex networks governing these interactions remains incomplete. The Drosophila melanogaster model has proven invaluable for dissecting hematopoiesis and innate immune cell function. As in vertebrates, Drosophila hematopoiesis occurs in two waves, with immune cells (hemocytes) distributed across the circulation, lymph gland, and sessile compartments, including epidermal-muscular sessile patches and hemocyte clusters near the eye-antennal epithelium. These sessile niches share features with vertebrate hematopoietic niches and tissue-specific microenvironments of resident myeloid cells, making Drosophila a powerful model for studying immune cell-tissue interactions. Our research identified an interaction between the phagocytic receptor Eater on hemocytes and Multiplexin (the Drosophila ortholog of human Collagen XV/XVIII) in niche basement membranes. This interaction is essential for establishing and maintaining sessile microenvironments. However, the distinct spatial organization of sessile compartments suggests that their establishment relies on complex molecular and cellular networks beyond the Mp-Eater axis. This project aims to: (1) define the microanatomy of Drosophila sessile niches, identifying structural relationships and regulatory interactions; (2) investigate niche development and dynamics, focusing on Mp-Eater interactions, regulatory networks, and immune cell exchange under homeostasis and stress; and (3) explore the functional roles of sessile niches in tissue development, immune cell plasticity, and organogenesis. Using genetics, advanced imaging, biochemical methods, and single-cell RNA sequencing, we will elucidate the molecular mechanisms of immune cell-niche interactions. By exploiting the functional conservation and experimental accessibility of the Drosophila model, we will gain insights into the physical and molecular architecture and signalling hierarchies that govern these interactions. These findings will advance the understanding of epithelial-immune crosstalk underlying immune cell plasticity, epithelial tissue integrity, and pathology.

• DFG Programme: Research Grants