Regulation of T cell expansion by antigen presentation dynamics
Regulation of T cell expansion by antigen presentation dynamics
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DOI：
10.1073/pnas.1812800116
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发表时间：
2019-03-26
影响因子：
11.1
通讯作者：
Wingreen, Ned S.
中科院分区：
文献类型：
--
作者：
Mayer, Andreas;Zhang, Yaojun;Wingreen, Ned S.
适应性免疫系统的一个基本特征是在免疫反应过程中抗原特异性淋巴细胞的增殖，形成大量的效应细胞池。必须对这种增殖进行调控，以确保对感染的有效反应，同时避免免疫病理。最近在小鼠身上的实验表明，特定克隆的T细胞对同源抗原的反应遵循与T细胞初始数量成反比的幂定律。在这里，我们表明，这种关系自然产生于一个模型，在该模型中，T细胞的扩张受到递呈抗原的衰退水平的限制。同样的模型也解释了观察到的T细胞增殖依赖于对抗原的亲和力和抗原注射的动力学。将该模型扩展到多个竞争抗原的T细胞克隆的扩增，我们发现高亲和力克隆可以抑制低亲和力克隆的增殖，从而提高反应的特异性。使用该模型推导出最优的疫苗接种方案，我们发现，指数级增加抗原剂量可以实现近乎最优的应答。因此，我们得出结论，提呈抗原的动力学是适应性免疫反应的大小和特异性的关键调节因素。
An essential feature of the adaptive immune system is the proliferation of antigen-specific lymphocytes during an immune reaction to form a large pool of effector cells. This proliferation must be regulated to ensure an effective response to infection while avoiding immunopathology. Recent experiments in mice have demonstrated that the expansion of a specific clone of T cells in response to cognate antigen obeys a striking inverse power law with respect to the initial number of T cells. Here, we show that such a relationship arises naturally from a model in which T cell expansion is limited by decaying levels of presented antigen. The same model also accounts for the observed dependence of T cell expansion on affinity for antigen and on the kinetics of antigen administration. Extending the model to address expansion of multiple T cell clones competing for antigen, we find that higher-affinity clones can suppress the proliferation of lower-affinity clones, thereby promoting the specificity of the response. Using the model to derive optimal vaccination protocols, we find that exponentially increasing antigen doses can achieve a nearly optimized response. We thus conclude that the dynamics of presented antigen is a key regulator of both the size and specificity of the adaptive immune response.