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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.

摘要