权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of the follicular T-cell response to autoimmunity

滤泡 T 细胞对自身免疫反应的调节

基本信息

批准号：
9199455
负责人：
HARVEY CANTOR
金额：
$ 43.33万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9199455
关键词：
Address Age Antibody Affinity Antibody Response Autoantibodies Autoimmune Diseases Autoimmune Responses Autoimmunity B-Lymphocytes Binding CD4 Positive T Lymphocytes Cell Differentiation process Cell Lineage Cells ChIP-seq Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Complex DNA Binding Domain Development Elements Ensure Epigenetic Process FOXP3 gene Gene Expression Gene Targeting Generations Genetic Genetic Programming Genetic Transcription Grant Helper-Inducer T-Lymphocyte Histone Deacetylase Impairment Infection Invaded Molds Molecular Molecular Genetics Mus Mutant Strains Mice Mutation NuRD complex Nucleosomes Pathway interactions Phenotype Process Production Protein Isoforms Reaction Recruitment Activity Regulation Regulatory T-Lymphocyte Repression Structure of germinal center of lymph node Systemic Lupus Erythematosus T cell response T-Lymphocyte T-Lymphocyte Subsets Tamoxifen Testing Vaccination autoreactive B cell base biochip defined contribution experimental study insight microbial mouse model novel therapeutic intervention osteopontin pathogen prevent programs response systemic autoimmune disease transcription factor

项目摘要

PROJECT SUMMARY The generation of high-affinity antibodies and avoidance of autoimmune responses after microbial infection or vaccination requires precise control of the germinal center (GC) reaction by follicular T-cell subsets. Follicular helper CD4+ T (TFH) cells induce GC formation and help GC B cells to produce protective antibody responses to invading pathogens. FoxP3+ follicular regulatory T (TFR) cells inhibit TFH-driven GC responses and prevent emergence of auto-reactive B-cells and autoantibody formation. A key element in stable differentiation of both TFH and TFR is expression of the antagonistic Bcl6–Blimp1 pair of transcription factors (TF). Our recent studies of TFH differentiation have revealed that (a) ICOS-dependent binding of OPN-i to the Bcl6-RD2 domain promotes association of Bcl6 with the Mi-2β nucleosome remodeling and histone- deacetylase complex (Mi2β–NuRD) and (b) this Bcl6-containing complex is essential for efficient repression of Blimp1, TFH lineage stability and repression of alternative TH fates. We examine the molecular basis of this process in SA1. Analysis of ICOS+ TFR has also revealed an association between OPN-i, Bcl6, and components of the Mi2β-NuRD complex. We test the hypothesis that OPN-i-dependent formation of the Bcl6–Mi-2β-NuRD complex regulates a common genetic program expressed by TFR and TFH cells. This will entail identification of shared genetic loci that are co-occupied by Bcl6 and Mi2-β-NuRD according to Bio-ChIP-Seq and “ChIP-reChIP” analyses (SA2). Finally, we define the mechanism that allows co-expression of the antagonistic Bcl6–Blimp1 transcription factors in TFR and the contribution of Blimp1 to stable development and function of TFR cells is addressed in SA3. These studies should provide new insight into the molecular control of TFH/TFR differentiation and establish a foothold for new therapeutic approaches to autoimmune disease.

项目总结