Active evasion of CTL mediated killing and low quality responding CD8+ T cells contribute to persistence of brucellosis.
Active evasion of CTL mediated killing and low quality responding CD8+ T cells contribute to persistence of brucellosis.
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DOI：
10.1371/journal.pone.0034925
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Splitter GA
中科院分区：
文献类型：
--
作者：
Durward M;Radhakrishnan G;Harms J;Bareiss C;Magnani D;Splitter GA
布鲁氏菌病是一种常见的人畜共患疾病，在世界许多地方仍然流行。剖析这种疾病期间的宿主免疫反应，有助于了解为什么布鲁氏菌病通常难以解决。我们使用布鲁氏菌表位特异性体内杀伤实验来研究CD8+ T细胞杀伤纯化致病性蛋白处理的靶标的能力。重要的是，我们发现致病蛋白TcpB通过抑制CD8+ T细胞杀死小鼠布鲁氏菌表位特异性靶细胞而成为适应性免疫逃避的新效应物。此外，BALB/c小鼠在一年多的时间里表现出活跃的布鲁氏菌感染，许多小鼠伴有以前未报道的泌尿生殖区局灶性感染。部分CD8+ T细胞在慢性布鲁氏菌病过程中表现出LFA-1hi， cd127 - hi， KLRG-1lo的CD8+ Tmem表型，而CD8+ T细胞池作为一个整体具有非常弱的多功能细胞因子反应，IFN-γ与TNFα和/或IL-2的共同表达减少，这是衰竭的标志。当分别研究这3种细胞因子的表达时，我们在感染后90天和180天观察到显著的IFN-γ表达。TNFα的表达在任何时候都没有明显超过或低于背景水平。IL-2的表达没有显著超过背景，但有趣的是，在感染后180天，IL-2的表达确实显著低于未感染小鼠。在急性感染期间，梅利特布鲁氏菌逃避和减弱适应性免疫，我们的研究结果为慢性布鲁氏菌病期间观察到的CD8+ T细胞应答缺陷提供了潜在的机制。
Brucellosis is a common zoonotic disease that remains endemic in many parts of the world. Dissecting the host immune response during this disease provides insight as to why brucellosis is often difficult to resolve. We used a Brucella epitope specific in vivo killing assay to investigate the ability of CD8+ T cells to kill targets treated with purified pathogenic protein. Importantly, we found the pathogenic protein TcpB to be a novel effector of adaptive immune evasion by inhibiting CD8+ T cell killing of Brucella epitope specific target cells in mice. Further, BALB/c mice show active Brucella melitensis infection beyond one year, many with previously unreported focal infection of the urogenital area. A fraction of CD8+ T cells show a CD8+ Tmem phenotype of LFA-1hi, CD127hi, KLRG-1lo during the course of chronic brucellosis, while the CD8+ T cell pool as a whole had a very weak polyfunctional cytokine response with diminished co-expression of IFN-γ with TNFα and/or IL-2, a hallmark of exhaustion. When investigating the expression of these 3 cytokines individually, we observed significant IFN-γ expression at 90 and 180 days post-infection. TNFα expression did not significantly exceed or fall below background levels at any time. IL-2 expression did not significantly exceeded background, but, interestingly, did fall significantly below that of uninfected mice at 180 days post-infection. Brucella melitensis evades and blunts adaptive immunity during acute infection and our findings provide potential mechanisms for the deficit observed in responding CD8+ T cells during chronic brucellosis.
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