Receptor Pre-Clustering and T cell Responses: Insights into Molecular Mechanisms.
Receptor Pre-Clustering and T cell Responses: Insights into Molecular Mechanisms.
复制标题
DOI：
10.3389/fimmu.2014.00132
复制
发表时间：
2014
影响因子：
7.3
通讯作者：
Molina-París C
中科院分区：
文献类型：
--
作者：
Castro M;van Santen HM;Férez M;Alarcón B;Lythe G;Molina-París C
由T细胞受体（TCR）介导的对由主要组织相容性复合物I类或II类分子（pMHC）呈递的病原体衍生肽的识别启动的T细胞活化显示出极好的特异性和敏感性，即使TCR-pMHC结合相互作用具有低亲和力。最近的实验工作表明，TCR预聚簇可能是T细胞可以实现如此高的敏感性的机制。TCR的未解决的化学计量使得TCR-pMHC结合和TCR触发成为一个悬而未决的问题。我们制定了一个数学模型来表征T细胞表面上的T细胞受体（TCR）的预聚簇，其动机是实验观察到的初始和记忆T细胞表面上的TCR簇的分布。我们扩展了最近推出的随机标准来计算T细胞反应的时间尺度，假设配体诱导的交联TCR是最小的信号单元。我们推导出一个近似公式的平均时间信号启动。我们的研究结果表明，预聚类减少了平均激活时间。然而，需要更多的机制来解释幼稚和记忆T细胞反应之间的差异。我们讨论了我们的研究结果的生物学意义，我们的方法与其他现有的数学模型的兼容性和互补性。
T cell activation, initiated by T cell receptor (TCR) mediated recognition of pathogen-derived peptides presented by major histocompatibility complex class I or II molecules (pMHC), shows exquisite specificity and sensitivity, even though the TCR–pMHC binding interaction is of low affinity. Recent experimental work suggests that TCR pre-clustering may be a mechanism via which T cells can achieve such high sensitivity. The unresolved stoichiometry of the TCR makes TCR–pMHC binding and TCR triggering, an open question. We formulate a mathematical model to characterize the pre-clustering of T cell receptors (TCRs) on the surface of T cells, motivated by the experimentally observed distribution of TCR clusters on the surface of naive and memory T cells. We extend a recently introduced stochastic criterion to compute the timescales of T cell responses, assuming that ligand-induced cross-linked TCR is the minimum signaling unit. We derive an approximate formula for the mean time to signal initiation. Our results show that pre-clustering reduces the mean activation time. However, additional mechanisms favoring the existence of clusters are required to explain the difference between naive and memory T cell responses. We discuss the biological implications of our results, and both the compatibility and complementarity of our approach with other existing mathematical models.