CD8 T cell antigen recognition during chronic infection

慢性感染期间CD8 T细胞抗原识别

• 批准号: 10582733
• 负责人: Brian D Evavold
• 金额: $ 64.69万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582733
• 关键词: Affinity; Antigen-Presenting Cells; Antigens; Area; Binding; Biology; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Characteristics; Chronic; Complex; DNA; Data; Environment; Equilibrium; Event; Exhibits; Goals; Immunity; Infection; Intervention; Kinetics; Length; Ligands; Lymphocytic choriomeningitis virus; MHC antigen; Measures; Membrane; Memory; Mus; Outcome; Parasitic infection; Peptide/MHC Complex; Phenotype; Plasmodium; Polyomavirus; Process; Proteins; Publishing; Reporter; Research; Role; Signal Transduction; Surface; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TCR Activation; Testing; Time; Virus Diseases; Work; acute infection; adaptive immune response; base; chronic infection; effector T cell; exhaust; functional outcomes; immune checkpoint blockade; innovation; insight; novel; pathogen; receptor; recruit; response; sensor technology; two-dimensional

Abstract/Summary Everyone is chronically infected by pathogens that are able to evade the host adaptive immune responses. Our work focuses on the process of antigen recognition by CD8 T cells during chronic viral and parasitic infections with the goal of determining how these infections avoid T cell immunity. Many chronic infections generate a robust CD8 effector response that ultimately results in compromised responses and exhausted CD8 T cells despite persistent levels of antigen. Antigen recognition is governed by the interaction of the T cell receptor (TCR) with antigenic peptide:MHC (pMHC). These proteins are found in the surface membranes of T cells and antigen presenting cells. Protein interactions that occur between opposing cells happen within two dimensional (2D) constraints that pertinently influence the kinetics of the interaction. Kinetic binding parameters such as 2D TCR affinity and bond lifetime for antigenic pMHC are critical for T cell activation and subsequently dictate T cell activity. Our revised R01 application builds on our previously published work and preliminary data that defines the importance of TCR affinity and bond lifetime for pMHC antigen as key parameters that determine T cell fate. The assessment of the dynamic interaction between the 2D-restricted TCR and pMHC is a novel and exciting area of research because we, and others, have found that T cells apply force through the TCR:pMHC bond resulting in alteration in the length of time of antigen recognition. Importantly, our work shows that an increase in bond lifetime under force is absolutely required for optimal T cell effector functions. Thus, we hypothesize that chronic infection leads to exhausted T cell responses through reduction in the bond lifetime and overall strength of antigen recognition. So far, we have generated compelling preliminary data during chronic viral and parasitic infections. The ensuing work will be undertaken through 3 specific aims that will: 1) Define T cell effector functions, affinity and bond lifetime under force during chronic infection, 2) Dissect the role of the CD8 coreceptor in antigen recognition, and 3) Correlate 2D affinity and bond lifetimes with defined effector functions. The innovative insights generated by our work will provide the base understanding of CD8 T cell activation/inactivation in the presence of persistent encounters with antigen. Thus in this application, we seek to understand how changes in 2D kinetics of antigen recognition distinguish competent effectors from incompetent exhausted CD8 T cells during chronic infections.

摘要/摘要 每个人都长期感染了能够逃避宿主自适应免疫反应的病原体。我们的 工作重点是在慢性病毒和寄生虫感染过程中CD8 T细胞抗原识别的过程 目的是确定这些感染如何避免T细胞免疫。许多慢性感染产生了 强大的CD8效应子响应最终导致响应受损和耗尽的CD8 T细胞 尽管抗原持续存在。抗原识别受T细胞受体的相互作用控制 （TCR）与抗原肽：MHC（PMHC）。这些蛋白质在T细胞的表面膜和 抗原呈现细胞。相反细胞之间发生的蛋白质相互作用发生在二维 （2D）约束会影响相互作用的动力学。动力学结合参数，例如2D 抗原PMHC的TCR亲和力和键寿命对于T细胞激活至关重要，随后决定T 细胞活性。我们修订的R01应用程序建立在我们先前发表的工作和初步数据的基础上 将TCR亲和力和键寿命对PMHC抗原的重要性定义为确定t的关键参数 细胞命运。评估2D限制的TCR和PMHC之间的动态相互作用是一种新颖，并且 令人兴奋的研究领域是因为我们和其他人发现T细胞通过TCR施加力：PMHC 粘结导致抗原识别时间长度的改变。重要的是，我们的工作表明 最佳T细胞效应子函数所需的粘结寿命在武力下的增加是必需的。因此，我们 假设慢性感染通过降低粘结寿命导致耗尽的T细胞反应 和抗原识别的总体强度。到目前为止，我们在期间已经生成了引人入胜的初步数据 慢性病毒和寄生虫感染。随后的工作将通过3个特定目标进行：1） 在慢性感染期间定义T细胞效应的功能，亲和力和键寿命，2）剖析 CD8共受体在抗原识别中的作用，3）与定义的2D亲和力和键寿命相关 效应器功能。我们工作产生的创新见解将提供对CD8 T的基础理解 在与抗原持续相遇的情况下，细胞激活/灭活。因此，在此应用程序中，我们 寻求了解抗原识别2D动力学的变化如何将有效的效应子与 在慢性感染期间，无能耗尽的CD8 T细胞。