In Silico and In Vitro Studies of T Cell Signaling

消除单核细胞增生李斯特菌需要T细胞识别单核细胞增生李斯特菌抗原。不 细胞活化是通过T细胞表面上的T细胞受体（TCP）与同源pMHC的结合而启动的 抗原呈递细胞（APC）上的配体。虽然大多数关于T细胞活化的工作都集中在 TCR与结合于MHC的抗原肽的相互作用，最近的工作表明， 内源性自身肽在与抗原肽的协同作用中起重要作用， 足够的信号来激活T细胞。这表明内源性肽的变异性可能起作用， 在决定感染的结果中起着关键作用。此外，内源性肽的作用表明， 新的方法来思考肽拮抗作用，这是一个仍然无法解释的现象。在此，我们建议 使用数学建模与遗传和生物化学实验，以提供新的见解，如何 内源性肽有助于触发T细胞活化的初始信号传导事件。我们建议 研究内源性pMHC配体在识别L. 单核细胞增多症我们还建议确定TCR信号刺激之间的相互作用， 内源性，激动剂和拮抗剂配体，以确定潜在的机制 体外拮抗作用最后，我们希望首次尝试建立一个研究抗原的模型， 体内拮抗作用我们相信，这些研究将有助于更好地了解免疫系统是如何 系统感知并消除病原体。

Elimination of Listeria monocytogenes requires the recognition of L monocytogenes antigens by T cells. T cell activation is initiated by the binding of the T cell receptor (TCP) on the T cell surface to cognate pMHC ligands on antigen presenting cells (APCs). While most work on T cell activation has focused on the interaction of the TCR with the antigenic peptide bound to MHC, recent work demonstrates that nonantigenic, endogenous self peptides play important roles in cooperating with antigenic peptides to allow for sufficient signaling to activate T cells. This suggests that variability of endogenous peptides could play a critical role in determining the outcome of an infection. In addition, the role of endogenous peptides suggests new ways to think about peptide antagonism, a phenomenon that is still unexplained. Here we propose to use mathematical modeling with genetic and biochemical experiments to lend new insights into how endogenous peptides contribute to the initial signaling events that trigger T cell activation. We propose to examine the role of endogenous pMHC ligands in mediating signaling during the recognition of L. monocytogenes. We also propose to determine the interplay between TCR signaling stimulated by endogenous, agonist, and antagonist ligands with a view toward determining the mechanism underlying antagonism in vitro. Lastly, we hope to for the first time try and establish a model for studying antigenic antagonism in vivo. We believe that these studies will lead to a better understanding of how the immune system sense and eliminates pathogens.