Type 1 diabetes (T1D) is driven by autoimmune destruction of pancreatic islets, where local interactions between islet myeloid cells and autoreactive T cells play a pivotal role in disease progression. However, the phenotypicdiversity and functional impact of distinct myeloid subsets within human islets remain poorly understood. Our preliminary data demonstrates that antigenic interactions between islet myeloid cells and T cells were suppressed by the efferocytic receptor, Mertk. This leads to decreased T cell activation and effector functions. In single–cell transcriptomic myeloid datasets from human islets, we found that TREM1, a potent inflammation amplifier, was the most upregulated gene between nondiabetic (ND) and T1D donors, suggesting that TREM1 signaling may contribute to local inflammation in the islet microenvironment. Importantly, TREM1 and MERTK can exert opposing effects on the NFkB pathway, with TREM1 promoting NFkB signaling and MERTK suppressing it. Thus, NFkB is a central signaling node that controls the balance between pro–inflammatory and immunoregulatory programs within islet myeloid cells.We hypothesize that TREM1⁺ myeloid cells promote T1D pathogenesis by producing pro–inflammatory cytokines and presenting islet antigens to stimulate autoreactive T cells, while efferocytic MERTK⁺islet macrophages constrain these responses by limiting antigen presentation and suppressing pro–inflammatory mediators. To test this, we will use human pancreatic slices in functional approaches. The specific aims will determine how modulating NFkB, TREM1, or MERTK signaling in human pancreas slices impacts myeloid cell antigen presentation, cytokine production, and T cell signaling and activation. Together, these studies will delineate how distinct myeloid–T cell interactions shape islet immunity and identify novel targets for potential myeloid–targeted therapeutic in T1D.
