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 每个人都被能够逃避宿主适应性免疫反应的病原体慢性感染。我们的 研究重点是慢性病毒和寄生虫感染期间CD8 T细胞识别抗原的过程 目的是确定这些感染是如何避免T细胞免疫的。许多慢性感染会产生 强大的CD8效应器反应，最终导致反应受损和CD8 T细胞耗尽 尽管体内的抗原水平一直很高。抗原识别受控于T细胞受体的相互作用 (TCR)抗原肽：MHC(PMHC)。这些蛋白质存在于T细胞的表面膜上， 抗原提呈细胞。发生在对立细胞之间的蛋白质相互作用发生在两个维度内 (2D)相关地影响相互作用的动力学的约束。动力学结合参数，如2D 抗原性pMHC的TCR亲和力和键寿命对T细胞激活至关重要，并随后决定T细胞 细胞活动。我们修订的R01应用程序建立在我们之前发布的工作和初步数据的基础上， 确定pMHC抗原的TCR亲和力和结合寿命的重要性是决定T的关键参数 细胞的命运。评估2D限制的TCR和pMHC之间的动态相互作用是一种新的和 令人兴奋的研究领域，因为我们和其他人已经发现T细胞通过TCR：pMHC施力 结合导致抗原识别时间长度的改变。重要的是，我们的工作表明， 为了发挥最佳的T细胞效应器功能，在作用力下增加键的寿命是绝对必要的。因此，我们 假设慢性感染通过缩短结合寿命导致耗尽的T细胞反应 和抗原识别的整体实力。到目前为止，我们已经生成了令人信服的初步数据 慢性病毒和寄生虫感染。后续工作将通过3个具体目标进行，这些目标将：1) 定义慢性感染期间T细胞效应器的功能、亲和力和结合寿命，2)解剖 CD8共受体在抗原识别中的作用，以及3)2D亲和力和结合寿命与定义的 效应器功能。我们的工作产生的创新见解将为我们对CD8 T的基本理解提供基础 在持续接触抗原的情况下，细胞激活/失活。因此，在此应用程序中，我们 试图了解抗原识别2D动力学的变化如何区分合格的效应者和 慢性感染时耗尽的CD8 T细胞。