Quantitative modeling of the phenotypic variability of individual T cells and the

描述（由申请人提供）：我们的长期目标是从理论上和实验上探索可靠的免疫应答如何从单个T细胞的不可靠应答中在系统水平出现。我们的第一个项目旨在探索关键信号蛋白表达水平的异质性如何在T细胞对配体的反应性中产生表型变异。我们还将探讨如何将这种信号反应的随机性转化为功能表型变异。我们的第二个目的是测试多重信号（例如T细胞配体和IL 15细胞因子）如何激活信号传导串扰，其调节关键信号传导蛋白的水平和/或活性，并使T细胞对自身衍生的配体产生高反应。我们的第三个目标是探讨细胞因子调节如何在单个细胞水平上整合抗原应答中的细胞变异性，以实现受调节的集体应答。该项目的重点是白细胞介素-2作为一种关键的细胞因子，控制效应T细胞之间的群体感应和调节T细胞的抑制。我们的方法从根本上是跨学科的伴随计算建模和实验测试。它包括进行和验证理论预测，以量化和控制免疫反应如何作为单个T细胞的动态和集体调节特性出现。公共卫生相关性：我们的项目重点是开发实验验证的T细胞激活计算机模型。我们的目标是确定可靠的免疫反应如何从单个T细胞的不可靠激活中动态出现。我们研究的长期影响是更好地控制对癌症和自身免疫疾病免疫疗法的免疫反应。

DESCRIPTION (provided by applicant): Our long-term goal is to probe theoretically and experimentally how reliable immune responses emerge at the system level from the unreliable responses of individual T cells. Our first project aims at probing how heterogeneity in the expression levels of key signaling proteins generates phenotypic variability in T cells' responsiveness to ligands. We will also probe how such stochasticity of signaling responses translates into functional phenotypic variability. Our second aim tests how multiplexed signals (e.g. T cell ligands and IL15 cytokine) can activate signaling crosstalks that modulate the levels and/or activity of key signaling proteins and make T cells hyperresponsive to self-derived ligands. Our third aim probes how cytokine regulation integrates cell variability in antigen response at the individual cell level towards a regulated collective response. This project focuses on Interleukin-2 as a critical cytokine that controls quorum sensing among effector T cells and suppression by regulatory T cells. Our approach is fundamentally interdisciplinary with concomitant computational modeling and experimental testing. It consists in making and validating theoretical predictions to quantify and control how immune responses emerge as dynamically- and collectively-regulated properties of individual T cells. PUBLIC HEALTH RELEVANCE: Our project focuses on developing experimentally-validated computer models of T cell activation. Our goal is to identify how reliable immune responses emerge dynamically from the unreliable activation of individual T cells. The long-term impact of our research is in a better control of immune responses towards immunotherapies for cancer and auto- immune disorders.