This project aims to uncover how macrophage dysregulation promotes autoimmune β–cell destruction. Our lab has identified distinct pancreatic macrophage subtypes that mediate localized immune control by regulating T cell activity.
Aim 1 will use single cell sequencing to comprehensively profile pancreatic macrophage subsets and their communication with T cells during immune homeostasis and in Type 1 Diabetes (T1D). Our lab has developed and optimized methods for pancreatic macrophage and T cell purification to enable high resolution analysis using cryopreserved pancreas cell fractions from the islet lab. Matched pancreas, spleen, and lymph node samples will be collected from 10 organ donors—5 with early–stage T1D or islet autoantibodies and 5 matched controls—through established organ procurement networks (nPOD and our lab). We will define the tissue–specific macrophage states in homeostasis and T1D. Macrophage–T cell interactions will be modeled using computational tools to identify key signaling pathways distinguishing islet versus exocrine communication and homeostatic versus autoimmune states.
Aim 2 will map the spatial distribution of pancreatic macrophages and their interactions with islets and T cells using multiplex imaging in donors with varying T1D status and genetic risk. Our lab has developed a custom multiplex panel for in situ labeling of pancreatic macrophage subtypes with distinct functions in controlling tissue repair and T cell activity. Formalin–fixed pancreas sections from 150 donors—including those with T1D, islet autoantibodies, and high/low T1D polygenic risk scores—will be imaged. We will use cutting edge computational spatial analysis tools to quantify the pancreatic macrophage subtypes and how T1D and T1D genetic risk factors impact their interactions with islets, exocrine pancreas and T–cells.
Together, these complementary approaches will reveal the molecular and spatial dynamics of macrophage–T cell interactions in the pancreas and how they are altered in T1D, providing insight into mechanisms of autoimmunity and potential immunotherapeutic targets.
