Suboptimal activation of antigen-specific CD4+ effector cells enables persistence of M. tuberculosis in vivo.
Suboptimal activation of antigen-specific CD4+ effector cells enables persistence of M. tuberculosis in vivo.
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DOI：
10.1371/journal.ppat.1002063
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发表时间：
2011-05
期刊：
影响因子：
6.7
通讯作者：
Ernst JD
中科院分区：
文献类型：
--
作者：
Bold TD;Banaei N;Wolf AJ;Ernst JD
对结核分枝杆菌的适应性免疫控制了进行性细菌生长和疾病，但不能根除感染。在M. tuberculosis感染小鼠肺部的CD4+ T细胞中，我们观察到很少有不经体外再刺激而产生IFN-γ的细胞。因此，我们假设结核分枝杆菌避免消除的一种机制是通过限制肺部感染部位CD4+效应T细胞的激活。为了验证这一假设，我们采用了th1极化的CD4+效应T细胞特异性结核分枝杆菌Ag85B肽25 （P25TCRTh1细胞），将其运输到感染小鼠的肺部，并表现出抗原依赖性IFN-γ的产生。在感染早期，约10%的P25TCRTh1细胞在体内产生IFN-γ；随着感染进展到慢性期，这一比例下降到<1%。细菌对fbpB（编码Ag85B）的下调有助于肺中效应T细胞活化的减少，因为在慢性期表达fbpB的结核分枝杆菌菌株在体内以更高的频率刺激P25TCRTh1效应细胞，这导致CD4+ T细胞依赖性的肺细菌负荷减少，延长了小鼠的存活时间。单独使用合成肽25也增加了内源性抗原特异性效应细胞的活化，减少了肺部的细菌负荷，而没有明显的宿主毒性。这些结果表明，CD4+效应T细胞在结核病中以次优频率被激活，并且通过提供一个或多个表位肽来增加肺部效应T细胞的激活可能是结核病治疗的一个成功策略。结核分枝杆菌甚至在产生抗原特异性CD4+和CD8+ T细胞反应的人类或动物宿主中引起持续感染。为了理解这一现象，我们测试了一种假设，即针对结核分枝杆菌感染产生的CD4+效应T细胞不能在肺部感染部位遇到它们的抗原。利用感染结核分枝杆菌的小鼠，以及体内CD4+ T细胞抗原依赖性激活的实验，我们发现，针对抗原85B肽25的多克隆CD4+和T细胞受体转基因CD4+ T细胞在肺部以低频率被激活。我们发现这部分是由于结核分枝杆菌抗原基因表达的下调，因为抗原基因的强制表达导致CD4+ T细胞的更高频率激活，以及CD4+ T细胞依赖性的细菌负担减少和感染小鼠的存活时间延长。我们还发现，给予抗原85B肽25（被高比例的M. tuberculosis特异性CD4+ T细胞识别）可以减少肺部的细菌负担，这表明刺激现有的抗原特异性CD4+ T细胞可能是治疗结核病的一种有希望的方法。
Adaptive immunity to Mycobacterium tuberculosis controls progressive bacterial growth and disease but does not eradicate infection. Among CD4+ T cells in the lungs of M. tuberculosis-infected mice, we observed that few produced IFN-γ without ex vivo restimulation. Therefore, we hypothesized that one mechanism whereby M. tuberculosis avoids elimination is by limiting activation of CD4+ effector T cells at the site of infection in the lungs. To test this hypothesis, we adoptively transferred Th1-polarized CD4+ effector T cells specific for M. tuberculosis Ag85B peptide 25 (P25TCRTh1 cells), which trafficked to the lungs of infected mice and exhibited antigen-dependent IFN-γ production. During the early phase of infection, ∼10% of P25TCRTh1 cells produced IFN-γ in vivo; this declined to <1% as infection progressed to chronic phase. Bacterial downregulation of fbpB (encoding Ag85B) contributed to the decrease in effector T cell activation in the lungs, as a strain of M. tuberculosis engineered to express fbpB in the chronic phase stimulated P25TCRTh1 effector cells at higher frequencies in vivo, and this resulted in CD4+ T cell-dependent reduction of lung bacterial burdens and prolonged survival of mice. Administration of synthetic peptide 25 alone also increased activation of endogenous antigen-specific effector cells and reduced the bacterial burden in the lungs without apparent host toxicity. These results indicate that CD4+ effector T cells are activated at suboptimal frequencies in tuberculosis, and that increasing effector T cell activation in the lungs by providing one or more epitope peptides may be a successful strategy for TB therapy. Mycobacterium tuberculosis causes persistent infection even in human or animal hosts that develop antigen-specific CD4+ and CD8+ T cell responses. To understand this phenomenon, we tested the hypothesis that the CD4+ effector T cells that are generated in response to M. tuberculosis infection fail to encounter their antigens at the site of infection in the lungs. Using mice infected with M. tuberculosis, and an assay of in vivo antigen-dependent activation of CD4+ T cells, we found that both polyclonal CD4+ and T cell receptor transgenic CD4+ T cells specific for antigen 85B peptide 25 are activated at low frequencies in the lungs. We found that this is due in part to downregulation of antigen gene expression by M. tuberculosis, as forced expression of the antigen gene resulted in higher frequency activation of CD4+ T cells, as well as CD4+ T cell-dependent reduction in bacterial burdens and prolonged survival of infected mice. We also found that administration of antigen 85B peptide 25, which is recognized by a high proportion of M. tuberculosis-specific CD4+ T cells, reduced the bacterial burden in the lungs, indicating that stimulation of existing antigen-specific CD4+ T cells may be a promising approach to therapy of TB.
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影响因子：
4.4
作者：
Banaiee, Niaz;Kincaid, Eleanor Z.;Ernst, Joel D.
通讯作者：
Ernst, Joel D.
结核分枝杆菌对抗原呈递的调节：Toll 样受体的作用。
DOI：
10.1038/nrmicro2321
发表时间：
2010-04
期刊：
Nature reviews. Microbiology
影响因子：
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作者：
通讯作者：
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影响因子：
7
作者：
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通讯作者：
Cooper AM
影响因子：
48
作者：
Buch, T;Heppner, FL;Waisman, A
通讯作者：
Waisman, A
影响因子：
15.9
作者：
Hinchey, Joseph;Lee, Sunhee;Porcelli, Steven A.
通讯作者：
Porcelli, Steven A.