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：
10066305
负责人：
HARVEY CANTOR
金额：
$ 42.95万
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 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10066305
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 Generations Genes 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 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 genomic locus insight microbial mouse model novel therapeutic intervention osteopontin pathogen pathogenic microbe prevent programs recruit 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.

项目摘要免疫后高亲和力抗体的产生和自身免疫反应的避免微生物感染或接种疫苗需要精确控制生殖中心（GC）反应由滤泡T细胞亚群组成滤泡辅助性CD 4 + T（TFH）细胞诱导GC形成并帮助 GC B细胞对入侵的病原体产生保护性抗体反应。FoxP 3+滤泡调节性T（TFR）细胞抑制TFH驱动的GC反应，并防止自身反应性 B细胞和自身抗体形成。TFH和TFR稳定分化的关键因素是拮抗性Bcl 6-Blimp 1对转录因子（TF）的表达。我们最近的研究已经揭示了（a）OPN-i与Bcl 6-RD 2的ICOS依赖性结合，结构域促进Bcl 6与Mi-2β核小体重塑和组蛋白- 脱乙酰酶复合物（Mi2β-NuRD）和（B）这种含Bcl 6的复合物对于 Blimp 1的有效抑制、TFH谱系稳定性和替代TH命运的抑制。我们在SA 1中检查该过程的分子基础。对ICOS+ TFR的分析还显示， OPN-1、Bcl 6和Mi2β-NuRD复合物的组分之间的关联。我们测试的假设Bcl 6-Mi-2β-NuRD复合物的OPN-1依赖性形成调节了一种新的细胞因子，由TFR和TFH细胞表达的共同遗传程序。这将需要确定共享的根据Bio-ChIP-Seq，由Bcl 6和Mi2-β-NuRD共同占据的遗传基因座，以及 “ChIP-reChIP”分析（SA 2）。最后，我们定义了允许共表达的机制， TFR中的拮抗性Bcl 6-Blimp 1转录因子以及Blimp 1对TFR稳定性的贡献 TFR细胞的发育和功能在SA 3中阐述。这些研究将提供新的深入了解TFH/TFR分化的分子控制，并为新的自身免疫性疾病的治疗方法。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Suppression of autoimmune disease after vaccination with autoreactive T cells that express Qa-1 peptide complexes.

使用表达 Qa-1 肽复合物的自身反应性 T 细胞接种疫苗后可抑制自身免疫性疾病。

DOI：
10.1172/jci20772
发表时间：
2004
期刊：
The Journal of clinical investigation.
影响因子：
0
作者：
Panoutsakopoulou,Vily;Huster,KatharinaM;McCarty,Nami;Feinberg,Evan;Wang,Rijian;Wucherpfennig,KaiW;Cantor,Harvey
通讯作者：
Cantor,Harvey

The immune response after hypoxia-ischemia in a mouse model of preterm brain injury.

DOI：
10.1186/s12974-014-0153-z
发表时间：
2014-09-05
期刊：
Journal of neuroinflammation
影响因子：
9.3
作者：
Albertsson AM;Bi D;Duan L;Zhang X;Leavenworth JW;Qiao L;Zhu C;Cardell S;Cantor H;Hagberg H;Mallard C;Wang X
通讯作者：
Wang X

Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: role of intracellular osteopontin.

DOI：
10.1016/j.immuni.2008.05.008
发表时间：
2008-07-18
期刊：
IMMUNITY
影响因子：
32.4
作者：
Shinohara, Mari L.;Kim, June-Ho;Garcia, Virgilio A.;Cantor, Harvey
通讯作者：
Cantor, Harvey

A narrow T cell receptor repertoire instructs thymic differentiation of MHC class Ib-restricted CD8+ regulatory T cells.

DOI：
10.1172/jci170512
发表时间：
2024-01-02
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
Kim, Hye-Jung;Nakagawa, Hidetoshi;Choi, John Y.;Che, Xuchun;Divris, Andrew;Liu, Qingshi;Wight, Andrew E.;Zhang, Hengcheng;Saad, Anis;Solhjou, Zhabiz;Deban, Christa;Azzi, Jamil R.;Cantor, Harvey
通讯作者：
Cantor, Harvey

Antibody-mediated blockade of the IL23 receptor destabilizes intratumoral regulatory T cells and enhances immunotherapy.