Suppression of cell-mediated immunity following recognition of phagosome-confined bacteria.
Suppression of cell-mediated immunity following recognition of phagosome-confined bacteria.
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DOI：
10.1371/journal.ppat.1000568
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发表时间：
2009-09
期刊：
影响因子：
6.7
通讯作者：
Portnoy DA
中科院分区：
文献类型：
--
作者：
Bahjat KS;Meyer-Morse N;Lemmens EE;Shugart JA;Dubensky TW;Brockstedt DG;Portnoy DA
单核细胞增多性李斯特菌是一种兼性胞内病原体，能够诱导对亚致死感染产生强大的细胞免疫反应。单核细胞增多性李斯特菌逃离吞噬小体进入宿主细胞胞浆的能力对于诱导CD8T细胞介导的长期保护性免疫是至关重要的。在这里，我们表明，限制在吞噬小体内的T细胞对单核细胞增多性李斯特氏菌的反应受损不仅是抗原提呈效率低下的结果，而且是适应性反应直接受到抑制的结果。这种抑制不仅限制了对液泡限制的单核细胞增多性乳杆菌的适应性反应，而且否定了对细胞质中细菌的反应。与单核细胞增多性李斯特菌菌株相比，吞噬小体受限和胞质单核细胞增多性李氏杆菌混合感染可阻止获得性免疫的产生和抗原特异性T细胞的有限扩增。限制在吞噬小体中的细菌抑制了促炎细胞因子的产生，并导致依赖于MyD88的IL-10的快速产生。在初次感染期间阻断IL-10受体或缺少MyD88可恢复保护性免疫。我们的研究表明，吞噬小体中微生物的存在可以通过拮抗炎症和产生保护性CD8T细胞所必需的信号通路，直接影响先天和获得性免疫反应。关于免疫系统如何区分致病微生物和非致病微生物，人们知之甚少。限制或预防细胞内病原体的感染需要激活先天免疫，从而产生识别和杀死受感染细胞的效应T细胞和记忆T细胞。研究人员目前正在测试致病微生物的减毒版本作为疫苗，试图在不导致疾病的情况下产生病原体特异性T细胞。不幸的是，减毒的微生物往往不能激发持久的保护性免疫。我们假设，减毒的细菌疫苗不能免疫，因为它们不能激活宿主固有免疫受体的刺激臂。然而，我们发现，这些减毒的细菌疫苗并不是简单地阻止激活免疫，而是产生抑制所需免疫反应的负面信号。这些研究可能解释为什么在无效疫苗中添加佐剂并不一定能提高免疫原性。此外，这些研究为开发不抑制所需免疫反应的减毒疫苗提供了一个框架。
Listeria monocytogenes is a facultative intracellular pathogen capable of inducing a robust cell-mediated immune response to sub-lethal infection. The capacity of L. monocytogenes to escape from the phagosome and enter the host cell cytosol is paramount for the induction of long-lived CD8 T cell–mediated protective immunity. Here, we show that the impaired T cell response to L. monocytogenes confined within a phagosome is not merely a consequence of inefficient antigen presentation, but is the result of direct suppression of the adaptive response. This suppression limited not only the adaptive response to vacuole-confined L. monocytogenes, but negated the response to bacteria within the cytosol. Co-infection with phagosome-confined and cytosolic L. monocytogenes prevented the generation of acquired immunity and limited expansion of antigen-specific T cells relative to the cytosolic L. monocytogenes strain alone. Bacteria confined to a phagosome suppressed the production of pro-inflammatory cytokines and led to the rapid MyD88-dependent production of IL-10. Blockade of the IL-10 receptor or the absence of MyD88 during primary infection restored protective immunity. Our studies demonstrate that the presence of microbes within a phagosome can directly impact the innate and adaptive immune response by antagonizing the signaling pathways necessary for inflammation and the generation of protective CD8 T cells. Little is understood about how the immune system distinguishes between pathogenic and non-pathogenic microbes. Limiting or preventing infections by intracellular pathogens requires the activation of innate immunity and the consequent generation of effector and memory T cells, which recognize and kill infected cells. Investigators are currently testing attenuated versions of pathogenic microbes as vaccines in an attempt to generate pathogen-specific T cells without causing disease. Unfortunately, attenuated microbes often fail to elicit long-lived protective immunity. We hypothesized that attenuated bacterial vaccines do not immunize because they fail to activate a stimulatory arm of host innate immune receptors. However, we found that these attenuated bacterial vaccines are not simply prevented from activating immunity, but rather generate a negative signal that inhibits the desired immune response. These studies may explain why the addition of an adjuvant to ineffective vaccines does not necessarily improve immunogenicity. Furthermore, these studies provide a framework for the development of attenuated vaccines that do not inhibit the desired immune responses.
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DOI：
10.1084/jem.20021910
发表时间：
2003-05-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Curtsinger JM;Lins DC;Mescher MF
通讯作者：
Mescher MF
影响因子：
3.1
作者：
Bahjat, Keith S.;Liu, Weiqun;Brockstedt, Dirk G.
通讯作者：
Brockstedt, Dirk G.
影响因子：
32.4
作者：
HARTY, JT;BEVAN, MJ
通讯作者：
BEVAN, MJ
免疫蛋白酶体塑造抗病毒CD8（+）T细胞在T细胞库水平和病毒抗原的表现下的免疫主导层次结构。
影响因子：
15.3
作者：
Chen, W;Norbury, C C;Cho, Y;Yewdell, J W;Bennink, J R
通讯作者：
Bennink, J R
影响因子：
4.4
作者：
Badovinac, VP;Harty, JT
通讯作者：
Harty, JT