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

描述（由申请人提供）：我正在寻求职业过渡奖，以协助我在流感感染模型中的免疫优势等级的研究。在我的研究生和博士后工作中，我分别在寄生和病毒模型中的宿主-病原体相互作用方面有很强的背景。虽然我的博士后工作的很大一部分集中在CD4+ T细胞在流感中的激活和扩增，我也开发了几个感染模型来研究免疫优势。在几乎所有类型的感染和肿瘤免疫模型中，在B细胞、CD4+ T细胞和CD8+ T细胞抗原特异性应答中都观察到免疫优势现象。目前还不确定为什么一个响应比其他响应占主导地位，但很明显，不止一个参数起作用。在BL/6小鼠流感感染模型中，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结果，表明前体频率和表位密度是流感模型中CD8+ 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，这限制了我们在体内模型中直接模拟它们如何影响免疫优势的尝试。在这个提议中，我试图测试我所产生的免疫优势的数学模型作为中心假设。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。

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.