Multiple mechanisms allow Mycobacterium tuberculosis to continuously inhibit MHC class II-mediated antigen presentation by macrophages
Multiple mechanisms allow Mycobacterium tuberculosis to continuously inhibit MHC class II-mediated antigen presentation by macrophages
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DOI：
10.1073/pnas.0500362102
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发表时间：
2005-03-22
影响因子：
11.1
通讯作者：
Kirschner, DE
中科院分区：
文献类型：
--
作者：
Chang, ST;Linderman, JJ;Kirschner, DE
先前的实验研究表明，结核分枝杆菌抑制许多与抗原呈递相关的巨噬细胞胞内过程，包括抗原加工、MHC II 类表达、MHC II 类分子的运输以及肽-MHC II 类结合。在这项研究中，我们调查了为什么观察到多种机制。具体来说，我们考虑多种机制可以达到什么目的，实验协议是否有利于某些机制的检测而不是其他机制，以及是否存在替代机制。通过使用巨噬细胞中抗原呈递的数学模型来追踪各种分子（包括细胞表面的肽-MHC II类复合物）的水平，我们表明针对MHC II类表达的机制可以有效抑制抗原呈递，但只有在延迟至少10小时后才有效。相比之下，针对其他细胞过程的机制的有效性是立竿见影的，但在某些条件下可能会减弱。因此，针对多个细胞过程可能代表结核分枝杆菌（以及其他倍增时间相对较长的病原体）维持抗原呈递持续抑制的最佳策略。此外，根据模型的敏感性分析，我们确定了此类病原体可能针对的其他细胞过程，以实现相同的效果，代表了潜在的新机制。
Previous experimental studies suggest that Mycobacterium tuberculosis inhibits a number of macrophage intracellular processes associated with antigen presentation, including antigen processing, MHC class II expression, trafficking of MHC class II molecules, and peptide-MHC class II binding. In this study, we investigate why multiple mechanisms have been observed. Specifically, we consider what purpose multiple mechanisms may serve, whether experimental protocols favor the detection of some mechanisms over others, and whether alternative mechanisms exist. By using a mathematical model of antigen presentation in macrophages that tracks levels of various molecules, including peptide-MHC class II complexes on the cell surface, we show that mechanisms targeting MHC class II expression are effective at inhibiting antigen presentation, but only after a delay of at least 10 h. By comparison, the effectiveness of mechanisms targeting other cellular processes is immediate, but may be attenuated under certain conditions. Therefore, targeting multiple cellular processes may represent an optimal strategy for M. tuberculosis (and other pathogens with relatively long doubling times) to maintain continuous inhibition of antigen presentation. In addition, based on a sensitivity analysis of the model, we identify other cellular processes that may be targeted by such pathogens to accomplish the same effect, representing potentially novel mechanisms.