CD8+ T Cell Exhaustion, Suppressed Gamma Interferon Production, and Delayed Memory Response Induced by Chronic Brucella melitensis Infection
CD8+ T Cell Exhaustion, Suppressed Gamma Interferon Production, and Delayed Memory Response Induced by Chronic Brucella melitensis Infection
复制标题
DOI：
10.1128/iai.01184-15
复制
发表时间：
2015-12-01
影响因子：
3.1
通讯作者：
Splitter, Gary A.
中科院分区：
文献类型：
--
作者：
Durward-Diloia, Marina;Harms, Jerome;Splitter, Gary A.
羊种布鲁氏菌是一种适应性很强的人畜共患病病原体，自有记载以来一直被认为是人类的祸害。在某些情况下，初始感染导致慢性和复发性布鲁氏菌病，导致严重的发病率和经济损失。B.对羊种病毒破坏适应性免疫记忆的认识很少。先前的研究表明，布鲁氏菌特异性CD 8（+）T细胞表达γ干扰素（IFN-γ），可以转变为长寿的记忆细胞，但不是多功能的。本研究采用B. Melitensis导致CD 8（+）T细胞耗竭，表现为程序性细胞死亡1（PD-1）和淋巴细胞活化基因3（LAG-3）表达以及IFN-γ产生的缺乏。B。与未感染小鼠的CD 8（+）细胞相比，产生IFN-γ的羊种白血病特异性CD 8（+）T细胞每个细胞表达的IFN-γ较少。在慢性感染期间鉴定了记忆前体（CD 8（+）LFA 1（HI）CD 127（HI）KLRG 1（LO））和长寿命记忆（CD 8（+）CD 27（HI）CD 127（HI）KLRG 1（LO））细胞。有趣的是，在过继转移后，接受慢性感染动物细胞的小鼠能够比接受急性感染或未感染供体细胞的小鼠更快地控制感染，尽管过继转移后，受攻击和未受攻击的受体中耗尽的CD 8（+）T细胞的比例增加。受攻击受体的CD 8（+）T细胞最初保留了转移前发现的IFN-γ产生受阻，并且在所有测试时间点（直至初次感染后30天）从未观察到急性感染小鼠的细胞转变为任一记忆亚群，表明记忆产生延迟。在这里，我们已经确定了布鲁氏菌反应性CD 8（+）T细胞的缺陷，使慢性持续感染。
Brucella melitensis is a well-adapted zoonotic pathogen considered a scourge of mankind since recorded history. In some cases, initial infection leads to chronic and reactivating brucellosis, incurring significant morbidity and economic loss. The mechanism by which B. melitensis subverts adaptive immunological memory is poorly understood. Previous work has shown that Brucella-specific CD8(+) T cells express gamma interferon (IFN-gamma) and can transition to long-lived memory cells but are not polyfunctional. In this study, chronic infection of mice with B. melitensis led to CD8(+)T cell exhaustion, manifested by programmed cell death 1 (PD-1) and lymphocyte activation gene 3 (LAG-3) expression and a lack of IFN-gamma production. The B. melitensis-specific CD8(+) T cells that produced IFN-gamma expressed less IFN-gamma per cell than did CD8(+) cells from uninfected mice. Both memory precursor (CD8(+) LFA1(HI) CD127(HI) KLRG1(LO)) and long-lived memory (CD8(+) CD27(HI) CD127(HI) KLRG1(LO)) cells were identified during chronic infection. Interestingly, after adoptive transfer, mice receiving cells from chronically infected animals were able to contain infection more rapidly than recipients of cells from acutely infected or uninfected donors, although the proportions of exhausted CD8(+) T cells increased after adoptive transfer in both challenged and unchallenged recipients. CD8(+) T cells of challenged recipients initially retained the stunted IFN-gamma production found prior to transfer, and cells from acutely infected mice were never seen to transition to either memory subset at all time points tested, up to 30 days post-primary infection, suggesting a delay in the generation of memory. Here we have identified defects in Brucella-responsive CD8(+) T cells that allow chronic persistence of infection.