Immunodominance hierarchies and compensation in influenza specific CD8+ T cell re

描述（由申请人提供）：我正在寻求一个职业过渡奖，以帮助我的研究免疫优势层次的流感感染模型。我有一个强大的背景，在宿主-病原体相互作用的寄生虫和病毒模型，从我的研究生和博士后工作，分别。虽然我的博士后工作的重要部分集中在流感中的CD 4 + T细胞活化和扩增，但我也开发了几种用于研究免疫优势的感染模型。在几乎所有类型的感染和肿瘤免疫模型中，在B细胞、CD 4 + T细胞和CD 8 + T细胞抗原特异性应答中观察到免疫显性现象。目前还不清楚为什么一个响应优于其他响应，但很明显，不止一个参数负责。在BL/6小鼠的流感感染模型中，我们观察到显著的免疫优势等级。我们的研究源于一系列的观察，表明前体频率和表位密度是流感模型中CD 8 + T细胞免疫优势等级的主要决定因素。然而，我们无法准确测量这两个参数，限制了我们直接模拟它们如何影响体内模型中的免疫优势的尝试。在这个建议中，我试图测试我作为中心假设产生的免疫优势的数学模型。为了验证这一假设，我建议开发更精确的定量技术来测量表位密度和前体频率。 了解免疫优势对于合理的疫苗设计和持续性感染（如HIV）的免疫治疗或抗肿瘤免疫治疗至关重要。目前，在体内估计一个“好”的表位依赖于经验观察和实验;我们几乎没有工具来预测表位，这些表位产生稳健的反应，将成功避免免疫逃逸，或具有保护性。该建议中的数学模型和参数测量应该允许对治疗设计的更前瞻性的方法，以及增加我们对CD 8 + T细胞应答的基本结构的理解。

DESCRIPTION (provided by applicant): I am seeking a career transition award to assist my studies of immunodominance hierarchies in the influenza infection model. I have a strong background in host-pathogen interactions in parasitic and viral models from my graduate and postdoctoral work, respectively. While a significant part of my postdoctoral work has focused on CD4+ T cell activation and expansion in influenza, I have also developed several infection models for the investigation of immunodominance. The phenomenon of immunodominance has been observed in B cell, CD4+ T cell and CD8+ T cell antigen-specific responses in virtually all types of infection and in tumor immunity models. It is still uncertain why one response dominates over other responses, however it is clear that more than one parameter is responsible. In the influenza infection model in BL/6 mice we observe a striking immunodominance hierarchy. Our study arises out of a series of observations suggesting precursor frequency and epitope density are the primary determinants of CD8+ T cell immunodominance hierarchies in the influenza model. However, our inability to accurately measure these two parameters has limited our attempts to directly model how they might influence immunodominance in in vivo models. In this proposal, I seek to test a mathematical model of immunodominance I have generated as the central hypothesis. To test this hypothesis, I propose the development of more quantitatively precise techniques for measuring both epitope density and precursor frequency. Understanding immunodominance is crucial to rational vaccine design and to immunotherapy for persistent infections such as HIV, or for anti-tumor immune treatments. Currently, estimating a "good" epitope in vivo relies on empirical observation and experimentation; we have few tools for predicting epitopes that generate a response that is robust, will successfully avoid immune escape, or be protective. The mathematical models in this proposal and parameter measurements should allow a more prospective approach towards therapeutic design as well increasing our understanding of the essential structure of CD8+ T cell responses.