CD8 T cell antigen recognition during chronic infection

摘要/概要 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 工作集中在慢性病毒和寄生虫感染期间CD 8 T细胞的抗原识别过程 目的是确定这些感染如何避免T细胞免疫。许多慢性感染会产生 稳健的CD 8效应子应答，最终导致应答受损和CD 8 T细胞耗竭 尽管抗原水平持续存在。抗原识别受T细胞受体的相互作用控制 (TCR)抗原肽：MHC（pMHC）。这些蛋白质存在于T细胞的表面膜中， 抗原呈递细胞发生在相对细胞之间的蛋白质相互作用发生在二维空间内， (2D)约束，有针对性地影响相互作用的动力学。动力学结合参数，如2D TCR对抗原性pMHC的亲和力和结合寿命对T细胞活化至关重要，并随后决定T细胞的活化。 细胞活性我们修改后的R 01应用程序建立在我们以前发表的工作和初步数据的基础上， 定义了TCR亲和力和pMHC抗原的键合寿命作为决定T 细胞命运2D限制性TCR和pMHC之间的动态相互作用的评估是一种新的， 这是一个令人兴奋的研究领域，因为我们和其他人发现T细胞通过TCR：pMHC施加力 导致抗原识别时间长度改变的键。重要的是，我们的工作表明， 对于最佳的T细胞效应子功能，在力作用下键寿命的增加是绝对需要的。因此我们 假设慢性感染通过缩短结合寿命导致T细胞应答衰竭 和抗原识别的整体强度。到目前为止，我们已经产生了令人信服的初步数据， 慢性病毒和寄生虫感染。接下来的工作将通过3个具体目标进行，这些目标将：1） 定义T细胞效应器功能、亲和力和慢性感染期间受力下的键寿命，2）解剖 CD 8辅助受体在抗原识别中的作用，以及3）将2D亲和力和键寿命与定义的 效应器功能。我们的工作所产生的创新见解将提供对CD 8 T的基本理解 在与抗原持续接触的情况下细胞活化/失活。因此，在本申请中，我们 寻求了解抗原识别的2D动力学变化如何区分有能力的效应子和 在慢性感染期间，CD 8 T细胞功能不全。

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.