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CD4+ T cell affinity for self and foreign antigens in the CNS

CD4 T 细胞对 CNS 中自身和外来抗原的亲和力

基本信息

批准号：
8471796
负责人：
Brian D Evavold
金额：
$ 31.89万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8471796
关键词：
Acute Address Adoptive Transfer Affinity Agreement Antigens Autoantigens Autoimmune Responses Autoimmunity Avidity Biological Assay CD4 Positive T Lymphocytes CD8B1 gene Cells Chronic Chronic Disease Chronic Phase Clinical Development Disease Disease Outcome Disease Progression Epitopes Experimental Autoimmune Encephalomyelitis Experimental Designs Frequencies Goals Grant Health Helper-Inducer T-Lymphocyte Histocompatibility Antigens Class II Human Immune Immune response In Vitro Inflammation Ionomycin Lymphocytic choriomeningitis virus Measurement Measures Mediating Methods Modeling Multiple Sclerosis Mus Myelin Nature Neuraxis Outcome Pathogenesis Pathology Patients Pattern Peptide/MHC Complex Peptides Phenotype Play Population Predictive Factor Process Proteins Reagent Regulation Regulatory T-Lymphocyte Reporting Research Role Severities Signal Transduction Site Staging Symptoms T cell response T-Cell Activation T-Lymphocyte Techniques Technology Testing Therapeutic Intervention Time Tissues Treatment Efficacy Viral Viral Antigens Virus Diseases Work base cell injury chronic autoimmune disease cytokine effective therapy exhaust immune activation improved in vivo innovation neurofilament novel oligodendrocyte-myelin glycoprotein outcome forecast pathogen prevent research study response tool

项目摘要

To date, our best tools for assessing the frequency and affinity of CD4+ T cells have been peptide:MHC (pMHC) tetramers or functional assays; neither of which effectively identify all of the responding cells to a particular antigen. This is in contrast to CD8+ T cells where these techniques prove more accurate. Generally, pMHC tetramers for class II antigens are difficult to produce and identify a small percentage of responding CD4+ T cells especially when antigen is derived from self proteins. The reason for this is that tetramer is based on affinity and if affinity is too low, then the tetramer is of limited use in assessing the response Functional responses also underestimate the number of antigen reactive CD4+ T cells. In the case of responses directed against myelin antigens for instance, the effector cytokine response is often determined using strong pharmacologic agents such as PMA and ionomycin, which hammer the T cell signaling cascade and may have little relevance to the cytokines being produced in response to antigen itself. To better assess the range of responding CD4+ T cells, we have begun to use micropipette based affinity assay. We report here a major advancement in assessment in the frequency and affinity of CD4+ T cells directed against myelin or viral antigens. Therefore for the first time, it is possible to track the range of affinities of a CD4+ T cells response during disease progression. Our preliminary findings have led to the following central hypothesis that the CD4+ T cell affinity profile directly impacts disease outcome and immune mediated tissue damage in the CNS. Three specific aims are proposed to test this hypothesis focused on CD4+ T cells specific for self antigen myelin oligodendrocyte glycoprotein and pathogen associated lymphocytic choriomeningitis virus antigens. Aim 1- Identify the affinity of CD4+ T cells over the course of chronic autoimmune disease and viral infection. Aim 2- Define the connection between T cell affinity and effector phenotype. Aim 3- Establish the contribution of high versus low affinity T cells in response to antigens found in the CNS.

迄今为止，我们评估CD4+ T细胞频率和亲和力的最佳工具是肽：MHC