Single Cell Genomics to Resolve Control of Immune Cell Function During Type 1 Diabetes

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PROJECT SUMMARY T cells specific for pancreatic beta cell antigens drive an autoimmune response leading to type 1 diabetes (T1D). During the onset of T1D, many immune cell types infiltrate into pancreatic islets, but the infiltration of each individual islet varies substantially within an individual mouse or human. Additionally, the interactions between immune cells and resident islet cells vary over the immune response within the microenvironment of an individual islet from infiltration and initial activation to a period of regulation before eventual destruction. A better understanding of factors that control autoreactive T cell function in the islets could lead to therapies for T1D that target the underlying mechanisms that cause disease. Based on our published work and new preliminary data, our central hypothesis is that autoreactive CD8+ T cell destruction of beta cells is determined by activation of the basic region leucine zipper (bZIP) transcription factors in response to the islet antigens and the local cellular microenvironment. We predict that these programs are differentially induced in CD8+ T cells by the cellular microenvironment of each individual islet. We propose two aims to test these predictions during onset of T1D in NOD mice using novel single cell functional genomics approaches. In Aim 1 we will determine the contribution of the bZIP transcription factors family to autoreactive T cell function in the pancreas. In Aim 2 we will determine impact of macrophages on the transcriptional programs of individual cells between separate pancreatic islet microenvironments. The expected results of our study will address unanswered questions about the fundamental mechanisms controlling T cell activity and immune cell interplay during autoimmune disease.