Epigenetic imprinting of follicular helper T cell fate and function in lupus

狼疮滤泡辅助 T 细胞命运和功能的表观遗传印记

• 批准号: 9974459
• 负责人: TERRI M. LAUFER
• 金额: $ 74.85万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-10 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9974459
• 关键词: ATAC-seq; Affect; Affinity; Antibodies; Antigen Presentation; Appearance; Autoantibodies; B-Lymphocytes; BLR1 gene; Biology; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Cellular biology; Chromatin; Clinic; Clinical; Code; DNA; Data; Defect; Development; Diagnostic; Disease; Epigenetic Process; Flow Cytometry; Future; Gene Expression; Generations; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Health; Helper-Inducer T-Lymphocyte; Human; Immunoglobulin Class Switching; Immunologics; Infection; Interleukin-17; Knowledge; Lupus; Lymphocytic choriomeningitis virus; Lymphoid; Lymphoid Tissue; Maintenance; Maps; Mediating; Metabolic Pathway; Molecular; Mouse Strains; Mus; Newly Diagnosed; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Predisposition; Process; Production; Publishing; Reaction; Regulator Genes; Regulatory Element; Rheumatology; SLEB1 gene; Secondary to; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Site; Specificity; Specimen; Structure of germinal center of lymph node; Susceptibility Gene; System; Systemic Lupus Erythematosus; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic Intervention; Tissue Differentiation; Tonsil; Tumor stage; chronic graft versus host disease; epigenome; epigenomics; experimental study; genome wide association study; imprint; improved; lupus prone mice; lymph nodes; mouse model; novel; peripheral blood; prevent; programmed cell death protein 1; programs; targeted biomarker; transcription factor

ABSTRACT The anti-nuclear autoantibodies (ANA) present in lupus are high-affinity, class-switched Abs that arise through T cell-dependent germinal center (GC) reactions. GC development and persistence is dependent on help from Follicular Helper CD4+ T cells (TFH). Although aberrant development and function of TFH drive disease in both SLE patients and murine models of lupus, the molecular and cellular pathways that initiate and reinforce the TFH fate remain poorly defined. This limits our ability to dissect the altered biology underlying lupus. Additionally, the study of human TFH has been hampered by lack of access to the secondary lymphoid tissues where they differentiate and function. Changes in the epigenetic code mediate the identity, specificity, stability, and function of differentiated CD4+ T helper (Th) cell subsets. Indeed, the epigenetic landscape may be a better indicator of the developmental and functional relationships amongst Th subsets than lineage-specific transcription factors. In preliminary data, our epigenetic analyses show that a significant number of lupus susceptibility GWAS SNPs map to regions of open chromatin in TFH, suggesting that altered TFH biology mediates a significant component of lupus genetic risk. We previously used unique murine models to define discreet stages of TFH differentiation: conventional DCs prime CD4+ T cells toward an unstable pre-TFH intermediate that expresses Bcl6 and CXCR5. Cognate T-B interactions drive the pre-TFH to produce IL-21, express PD-1, and repress production of IL-17. Preliminary epigenetic analyses confirm that pre-TFH are not fully committed to the TFH fate and show that we can identify a B cell-dependent module. However, B cell MHCII expression--with no requirement for DC priming--is sufficient for TFH differentiation in immunological settings similar to lupus. The proposal will utilize unique murine models and primary human cells to establish the epigenetic roadmap that defines commitment to the TFH fate. Lupus-prone mice with limited expression of MHCII will be utilized to define how sequential interactions between CD4+ T cells and DCs followed by B cells mediate changes in the epigenetic code. ATAC-Seq analyses of pre-TFH and TFH will identify the regulatory cascades, transcription factor programs, and metabolic pathways that are regulated by DCs and B cells during TFH differentiation. Secondly, we will build on these analyses to define how lupus disrupts this transcriptional and functional program. Does lupus: 1. alter the requirement for sequential cDC and B cell antigen presentation in the differentiation and maintenance of TFH? or 2. disrupt the epigenetic landscape of TFH differentiation and commitment? These experiments should identify the epigenetic signatures that 1. Define the B cell contribution to TFH differentiation and 2. Distinguish TFH in lupus and health controls. These results will provide the framework for future therapeutic interventions to ameliorate disease.

摘要