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

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Principal Investigator: Rachel S Friedman
Organization: NATIONAL JEWISH HEALTH
Fiscal Year: 2024
Award: $243,594
Funding agency: National Institute of Allergy and Infectious Diseases

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.

Terms: <ATAC sequencing><ATAC-seq><ATACseq><Address><Antigens><Assay><Assay for Transposase-Accessible Chromatin using sequencing><Autoantigens><Autoimmune Diseases><Autoimmune Responses><Autoimmune Status><Autoimmunity><Autologous Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><B9 endocrine pancreas><Bar Codes><Basal Transcription Factor><Basal transcription factor genes><Beta Cell><Bioassay><Biological Assay><Brittle Diabetes Mellitus><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancers><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Immune Function><Cellular Physiology><Cellular Process><Chronic><Chronic Disease><Chronic Illness><Clinical><DNA><Data><Deoxyribonucleic Acid><Disease><Disease Progression><Disorder><Endocrine Pancreas><Exposure to><Expression Signature><Family><Gene Expression Profile><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><Genomic approach><Goals><Human><Humulin R><IDDM><Immune><Immune infiltrates><Immune response><Immunes><Immunological response><Inbred NOD Mice><Individual><Infection><Infiltration><Insulin><Insulin Cell><Insulin Secreting Cell><Insulin-Dependent Diabetes Mellitus><Islands of Langerhans><Islet Cell><Islets of Langerhans><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Leucine Zippers><Link><Macrophage><Malignant Neoplasms><Malignant Tumor><Methods><Mice><Mice Mammals><Modern Man><Molecular><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Mφ><NOD Mouse><Nesidioblasts><Non-Obese Diabetic Mice><Nonobese Diabetic Mouse><Novolin R><Outcome><Pancreas><Pancreatic><Pancreatic Islets><Pancreatic beta Cell><Pancreatic β-Cell><Pars endocrina pancreatis><Pathogenesis><Pattern><Population><Protocol><Protocols documentation><Publishing><RNA Expression><Receptor Protein><Regular Insulin><Regulation><Resolution><Self-Antigens><Structure of beta Cell of islet><Subcellular Process><Sudden-Onset Diabetes Mellitus><T cell infiltration><T cell regulation><T cell response><T-Cells><T-Lymphocyte><T1 DM><T1 diabetes><T1D><T1DM><T8 Cells><T8 Lymphocytes><Techniques><Testing><Transcription><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><Virus><Work><advanced disease><advanced illness><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><autoimmune condition><autoimmune disorder><autoimmune reactivity><autoimmunity disease><autoreactive T cell><autoreactivity><barcode><cell type><chronic disorder><cytokine><disease control><disorder control><exhaust><exhaustion><experiment><experimental research><experimental study><experiments><functional genomics><gene expression pattern><gene expression signature><genomic effort><genomic strategy><host response><immune cell infiltrate><immune function><immune system response><immunogen><immunoresponse><insulin dependent diabetes><insulin dependent diabetes mellitus onset><insulin dependent type 1><islet><islet progenitor><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><malignancy><mouse model><murine model><neoplasm/cancer><non-obese diabetic (NOD) mice><nonobese diabetic (NOD) mice><novel><pancreas beta cell><pancreas β cell><pancreatic b-cell><programs><receptor><resolutions><response><scATAC sequencing><scATAC-seq><scRNA-seq><self-reactive T cell><single cell ATAC-seq><single cell ATAC-sequencing><single cell Assay for Transposase Accessible Chromatin sequencing><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell genomics><single cell sequencing assay for transposase accessible chromatin><single cell transcriptomic profiling><single-cell Assay for Transposase-Accessible Chromatin with sequencing><single-cell RNA sequencing><single-cell assay for transposase-accessible chromatin using sequencing><single-cell assay for transposase-accessible chromatin-seq><therapeutic target><thymus derived lymphocyte><transcription factor><transcriptional profile><transcriptional signature><tumor><type 1 diabetes onset><type I diabetes><type one diabetes><β-cell><β-cells><βCell>