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Determinants of follicular helper T cell expansion in lupus

狼疮滤泡辅助 T 细胞扩张的决定因素

基本信息

批准号：
10644534
负责人：
Laurence Morel
金额：
$ 63万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10644534
关键词：
Affect Affinity Autoantibodies Automobile Driving B-Lymphocyte Subsets B-Lymphocytes BLR1 gene CD4 Positive T Lymphocytes Cell Differentiation process Cell physiology Cells Congenic Mice Cues Data Diet Disease Disease Outcome Drug or chemical Tissue Distribution Environmental Impact Environmental Risk Factor Exhibits Frequencies Genes Genetic Genetic Determinism Genome Glucose Glutamine Glycolysis Health Helper-Inducer T-Lymphocyte Human ITGAX gene Immunoglobulin A Immunoglobulin Class Switching Investigation Knowledge Light Lupus Metabolic Metabolic Pathway Metabolism Modeling Molecular Mus Norleucine Outcome Pathway interactions Patients Peripheral Production Reagent SLEB1 gene SLEB3 gene Severities Severity of illness Spleen Susceptibility Gene Systemic Lupus Erythematosus T-Lymphocyte Subsets Testing Therapeutic Tryptophan Tryptophan Metabolism Pathway Validation Variant autoreactivity base cohort congenic dietary experimental study fecal microbiota follow-up genetic signature gut dysbiosis gut microbiota improved in vitro Assay in vivo innovation lupus prone mice metabolome metabolomics microbial microbiome mouse model novel pathogenic autoantibodies programmed cell death protein 1 response solute synergism transcriptome transcriptome sequencing transcriptomics

项目摘要

Project Summary/Abstract The expansion of follicular helper (Tfh) cells and related subpopulations is correlated with the severity of human lupus disease and is shared by all lupus-prone mouse models. However, the mechanisms for the expansion of Tfh cells in lupus are largely unknown. Thus, the objective of this proposal is to shed new light on the mechanisms that are responsible for Tfh cell expansion in lupus using innovative cellular and molecular approaches based on the obtained data from the B6.Sle1.Sle2.Sle3 triple congenic (TC) murine model of lupus. Accordingly, we have identified genetic, as well as microbial and metabolic determinants that modulate lupus Tfh cell expansion. Transferring the perturbed gut microbiota of lupus mice into mouse host crucially contributed to Tfh cell expansion. Additionally, an altered tryptophan (Trp) metabolism also enhanced Tfh cell expansion, which was reduced by manipulating dietary Trp levels in mice. Finally, inhibiting glycolysis with 2-deoxi-D-glucose (2DG), or glutaminolysis with 6-Diazo-5-oxo-L-norleucine (DON) functionally diminished lupus Tfh cell differentiation. Our hypothesis is that the expansion of Tfh cells implicated in lupus integrates cues from susceptibility genes, dysregulated microbiome and environmental metabolites. In support of this hypothesis, our data demonstrate that TC Tfh cells possess a novel metabolic gene signature, potentially driving the autoreactive Tfh cell expansion directed by a unique metabolic flux. Thus, we propose combining the analyses of Tfh cell transcriptome and metabolome in response to variations of the aforementioned cues as a means to elucidate the involved molecular mechanisms, singly or in combination, impacting the fate of Tfh cells in lupus. We also propose to investigate the effects of genetic and environmental determinants functionally affecting Tfh cells on two B cell subsets, CD11c+Tbet+ B cells (ABCs) and IgA+ B cells. To proceed, the following Specific Aims are proposed. 1. To explore the mechanisms by which lupus susceptibility genes modulate the Tfh cell transcriptome and metabolome in the two unrelated TC and (NZW x BXSB.Yaa)F1 lupus models. 2. To identify the impact of environmental factors on the Tfh transcriptome and metabolome in TC mice. And 3. To elucidate the molecular mechanisms implicated in the expansion of Tfh cells in lupus patients. Obtained results from these mechanistic experiments will be the first in-depth investigation of Tfh cell expansion directed by environmental and genetic determinants, which may be reprogrammed for a sustainable therapeutic strategy to perhaps improve lupus patients' health.

项目总结/文摘