Self-organization of T lymphocyte activation into collective immune responses

描述(由申请人提供)：我们的项目是一项实验驱动的建模工作，旨在探索适应性免疫系统中T淋巴细胞之间的细胞间通信。T淋巴细胞依靠细胞因子交流将单个细胞的激活转化为群体水平上的集体同步反应。因此，调节性T(Treg)细胞是免疫反应的关键组成部分，通过与效应性T(Treg)细胞竞争可溶性细胞因子，可以仲裁T细胞激活的方方面面(从抗原信号到分化)。我们推测，Treg细胞对细胞间通讯细胞因子的缓冲创造了一个动态障碍，Tef细胞必须克服这个障碍才能验证和追求自己的激活。我们将用三个项目来验证这一猜想。1)我们将模拟如何通过淋巴细胞趋化性调节抗原的长期结合，从而在TJeff细胞之间介导抗原识别和克隆选择。2)我们将模拟Treg细胞如何竞争TJeff细胞所依赖的炎性细胞因子，以便共同同步它们的激活状态和分化。3)我们将设计和测试使用微调细胞因子传递和阻断的淋巴细胞社会相互作用的有针对性的操作，作为一种有前景的免疫治疗方法。我们的方法结合了体外和体内T淋巴细胞激活的单细胞水平的定量表征和生物化学显式计算模型。我们的项目将开发一个经过实验验证的免疫系统细胞间通讯的定量模型，以优化针对临床应用的靶向细胞因子操作。相关性：通过细胞因子注射和阻断来扰乱淋巴细胞与淋巴细胞的通讯是临床免疫治疗领域很有希望的途径。为此，需要免疫学中的定量方法来模拟和利用T细胞激活的动态和组合复杂性。该项目旨在建立一个量化框架，以模拟和测试免疫系统中调节性T细胞和效应性T细胞之间平衡的各种扰动。

DESCRIPTION (provided by applicant): Our project is an experimentally driven modeling effort to probe cell-cell communications among T lymphocytes in the adaptive immune system. T lymphocytes rely on cytokine communications to translate individual cell activation into collectively synchronized responses at the population level. Accordingly, regulatory T (Treg) cells are critical components of the immune response that can arbitrate every aspect of T cell activation (from antigen signaling to differentiation), through competition with effector T (Teff) cells for soluble cytokines. We conjecture that the buffering of cell-cell communication cytokines by Treg cells creates a dynamic hurdle that Teff cells must overcome to validate and pursue their own activation. We will test this conjecture with three projects. 1) We will model how regulation of long-term engagement of antigens through lymphocyte chemotaxis mediates antigen discrimination and clonal selection among Teff cells. 2) We will model how Treg cells compete for inflammatory cytokines upon which Teff cells rely, in order to collectively synchronize their activation status and differentiation. 3) We will design and test targeted manipulations of lymphocytes social interactions using fine- tuned cytokine delivery and blocking, as a promising method for immunotherapy. Our method combines quantitative in vitro and in vivo single-cell level characterization of T lymphocyte activation with biochemically explicit computational modeling. Our project will develop an experimentally validated quantitative model of cell-cell communications in the immune system to optimize targeted cytokine manipulations towards clinical applications. RELEVANCE: Perturbations of lymphocyte-lymphocyte communications through cytokine injection and blocking are promising avenues in the field of clinical immunotherapies. For this, quantitative approaches in immunology are required to model and harness the dynamic and combinatorial complexity of T cell activation. This project aims at building a quantitative framework to model and test varied perturbations of the balance between regulatory T cells and effector T cells in the immune system.