Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime

解构 T 细胞抗原识别：亲和力与键寿命的分离

基本信息

批准号：
10681989
负责人：
Brian D Evavold
金额：
$ 71.79万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681989
关键词：
3-Dimensional Address Affect Affinity Antigen-Presenting Cells Antigens Applications Grants Automobile Driving Biological Assay Biophysics CD8-Positive T-Lymphocytes Cell Survival Cell membrane Cell physiology Cell surface Cells Cellular biology Data Development Engineering Equation Goals IL17 gene IL2RA gene Immune response In Situ Infection Infectious Agent Influenza Interferon Type II Interleukin-10 Interleukin-2 Joints Knowledge Ligands Listeria Lymphocytic choriomeningitis virus MHC Interaction MHC antigen Measures Mediating Membrane Memory Methods Mind Modeling Mus OX40 Outcome Peptide/MHC Complex Peptides Peripheral Phenotype Plasmodium Play Proteins Proxy Publishing Receptor Signaling Regulatory T-Lymphocyte Reporter Role Signal Transduction Surface T cell response T-Cell Receptor T-Lymphocyte TCR Activation Technology Thymocyte Development Tissues Translating Work biophysical properties complementarity-determining region 3 driving force functional outcomes microbial genome novel programmed cell death protein 1 response segregation two-dimensional

项目摘要

Abstract Recognition of antigen is the first critical step required in triggering T cell survival, expansion, development of effector functions, and transition to memory. In a joint project between the Evavold and Williams labs, we will determine how T cell receptor (TCR) and peptide:MHC (pMHC) affinity, bond lifetimes, and force magnitude define T cell phenotype. The proposed work is therefore impactful as it begins to delineate the role each of these parameters play in the rich T cell biology associated with TCR signal strength. To date, the concept of TCR strength of signal has generally been described with three-dimensional SPR affinity in mind and measured via representative surface markers, pMHC tetramers, and functional readouts. In contrast to these methods, our studies depend on the analysis of TCR and pMHC interactions at the surface of the cell membrane using novel assays that define the in-situ two-dimensional contact that occurs between T cells and APCs during antigen recognition. The preliminary work has discovered that bond lifetime and level of force as opposed to affinity provides the major driving force for phenotypic fate. The three specific aims will redefine the concept of TCR strength of signal, dissect affinity from bond lifetime, and determine outcomes of low affinity TCRs during infection. Currently, the TCR affinity and bond lifetime for pMHC are unknown for many T cell responses, limiting our knowledge on how T cell mediated responses are triggered and how affinity and bond lifetime are translated into TCR strength of signal and effector phenotypes. Therefore, our work will prove insightful by addressing the discrepancy between affinity based predictions and actual T cell functional outcomes.

抽象的识别抗原是触发T细胞存活，膨胀，发展的第一个关键步骤效应器功能，并过渡到内存。在《逃亡者》和威廉姆斯实验室之间的联合项目中，我们将确定T细胞受体（TCR）和肽：MHC（PMHC）亲和力，键寿命和力幅度如何定义T细胞表型。因此，拟议的工作具有影响力，因为它开始描述每个角色这些参数在与TCR信号强度相关的丰富T细胞生物学中起作用。迄今为止，通常用三维SPR亲和力描述了信号的TCR强度通过代表性的表面标记，PMHC四聚体和功能读数测量。与这些相反方法，我们的研究取决于细胞表面TCR和PMHC相互作用的分析膜使用定义T细胞之间发生的原位二维接触的新颖测定法抗原识别期间的APC。初步工作发现债券的寿命和力量是与亲和力相反，为表型命运提供了主要的驱动力。这三个具体目标将重新定义信号的TCR强度的概念，从键寿命中解剖亲和力，并确定低亲和力的结果感染期间的TCR。目前，PMHC的TCR亲和力和键寿命在许多T细胞中都是未知的响应，限制了我们关于如何触发T细胞介导的响应以及如何亲和力和联系的知识寿命被转化为信号和效应子表型的TCR强度。因此，我们的工作将证明通过解决基于亲和力的预测与实际T细胞功能之间的差异来有见地结果。