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B-cell-intrinsic MHCII Signaling is a Diversifying Force of Selection on IgA Repertoires and the Gut Microbiota

B 细胞固有的 MHCII 信号传导是 IgA 库和肠道微生物群选择的多样化力量

基本信息

批准号：
10614060
负责人：
Jason L Kubinak
金额：
$ 40.41万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-25 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614060
关键词：
Ablation Address Adoptive Transfer Affinity Antibodies Antibody Affinity Antibody Response Antigen Presentation Automobile Driving B-Lymphocytes Benign Bone Marrow CD4 Positive T Lymphocytes Cell Communication Cell Compartmentation Chimera organism Chronic Clone Cells Congenic Mice Data Defect Dependence Ecology Evolution Exons Extravasation Generations Genetic Polymorphism Genetic Variation Genotype Germ-Free Gut associated lymphoid tissue Health Health Promotion Heterozygote Histocompatibility Histocompatibility Antigens Class II Human IL7R gene IgA Deficiency Immune response Immune system Immunoglobulin A Immunologic Memory Individuality Inflammation Integration Host Factors Knowledge Link Lymphocyte MHC Class II Genes Mediating Memory Modeling Mucous Membrane Pathologic Peyer&apos s Patches Phenotype Physiology Plasma Cells Play Population Process Promoter Regions Rag1 Mouse Reaction Role Shapes Signal Transduction Single Nucleotide Polymorphism Map Structure of germinal center of lymph node Surface T-Cell Development T-Lymphocyte Testing Tissues Vertebrates Visual Work antigen binding commensal bacteria congenic density dysbiosis experimental study fitness gut microbiota host microbiota immune activation innovation microbial colonization microbial community microbiota microorganism antigen mouse model novel response systemic inflammatory response

项目摘要

Project Summary T-cell-dependent (TD) immunoglobulin A (IgA) responses regulate the composition of the gut microbiota. How B-cell-intrinsic MHCII signaling, which is central to the development of TD IgA responses, influences host- microbiota interactions is unknown. MHCII is widely assumed to promote clonal diversity in effector lymphocyte populations, but this has not been tested. Here, we present evidence in support of the argument that B cell- intrinsic MHCII signaling controls GC dynamics, IgA repertoire diversity, and microbiota composition. Additionally, evidence from our experiments also indicate that both B-cell-intrinsic ablation of MHCII and specific MHC genotypes are associated with enhanced bacterial dissemination from the gut. Based on these observations and previous work by Dr. Kubinak, this R01 seeks to address the hypothesis that B-cell-intrinsic MHCII signaling is a diversifying force of selection promoting clonal diversity in IgA plasma cell pools and individuality in microbiota composition. The objective of Specific Aim #1 is to define the B-cell-intrinsic role of MHCII during GC reactions in the gut; specifically focusing on its role in shaping plasma cell repertoire diversity. A 'Confetti' mouse model will be used to visually demonstrate the effect of MHCII ablation on GC B cell clonal diversity in the gut. IgH sequencing will be used to determine the effect of MHCII polymorphisms and MHC heterozygosity on IgA repertoire diversity in the gut. scRNA sequencing will be used to determine how MHCII influences overlap in clonal diversity between mucosal and systemic plasma cell pools. RAG1-/- bone marrow (BM) chimeras will be used to quantify the effect of MHCII on cross-seeding of gut-derived plasma cells into the BM. Reciprocal BM chimeras will be used to determine the necessity/sufficiency of defects in B-cell-intrinsic MHCII in regulating bacterial dissemination from the gut. The objective of Specific Aim #2 is to test that microbiota composition is an MHCII-dependent phenotype. RAG1-/- and RAG1-/-IL7R-/- BM chimeras will be used to determine the role gut peyer's patches play in driving MHCII-mediated IgA selection in the gut. Microbial colonization experiments in germfree GF RAG1-/- BM chimeras will determine the effect of B-cell-intrinsic MHCII on IgA-targeting of commensal bacteria. A RAG1-/- adoptive transfer model will be used to determine if MHCII surface density influences IgA-mediated targeting of commensals and microbiota composition. Finally, a novel germfree MHC congenic model will be used to explicitly define the role IgA plays in driving individuality in microbiota composition. Results from these studies will address the B-cell-intrinsic role of MHCII in regulating mucosal IgA responses, microbiota composition, and host health. This is a critical gap in our knowledge that is highly relevant to human health. IgA deficiency is the most common form of antibody-deficiency in humans, is strongly linked to genetic variation in MHCII genes, and has been shown to result in dysbiosis that is associated with chronic inflammation. Experiments outlined here are the first to address how MHC genotype influences microbiota composition and bacterial leakage from the gut, a potent driver of chronic immune activation.

项目总结