Differential regulation of effector- and central-memory responses to Toxoplasma gondii Infection by IL-12 revealed by tracking of Tgd057-specific CD8+ T cells.
Differential regulation of effector- and central-memory responses to Toxoplasma gondii Infection by IL-12 revealed by tracking of Tgd057-specific CD8+ T cells.
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DOI：
10.1371/journal.ppat.1000815
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发表时间：
2010-03-19
期刊：
影响因子：
6.7
通讯作者：
Yap GS
中科院分区：
文献类型：
--
作者：
Wilson DC;Grotenbreg GM;Liu K;Zhao Y;Frickel EM;Gubbels MJ;Ploegh HL;Yap GS
在弓形虫感染期间，先天吞噬细胞产生促炎细胞因子 IL-12，驱动产生 IFN-γ 的效应 T 细胞的分化。然而，IL-12 在调节小鼠弓形虫病期间记忆 CD8+ T 细胞分化和功能中的作用尚不清楚。为了追踪记忆 CTL 的发育，我们鉴定了一种新的 H-2Kb 限制性 CTL 群体，对弓形虫抗原 tgd057 具有特异性。 Tgd057特异性CTL是通过疫苗接种和自然口服感染诱导的，并且是多克隆CTL群体的代表。 Tgd057 特异性初级效应细胞需要 IL-12 来分化 KLRG1+ 效应子亚群，并响应寄生虫感染细胞的再刺激而产生 IFN-γ，但不需要同源肽的再刺激。初级反应期间 IL-12 缺乏的影响深深地印在记忆 CTL 上，记忆 CTL 继续显示出细胞数量、KLRG1+ 效应子记忆亚群分化和 IFN-γ 回忆反应方面的缺陷。重要的是，在没有IL-12的情况下分化的分离的CD62Lhi KLRG1-CD8+ T细胞产生产生IFN-γ的次级tgd057特异性效应细胞的能力得到增强。我们的数据首次证明了 IL-12 信号传导对中央记忆 CTL 区室质量的负面影响。因此，尽管IL-12在促进效应细胞分化方面发挥有益作用，但在CTL启动过程中过度暴露于IL-12可能会通过降低中枢记忆CTL反应的适应性来限制长期保护性免疫的发展。 弓形虫是一种普遍存在的原生动物寄生虫，会导致免疫功能受损的人患上严重疾病。众所周知，CD8+ T 细胞对于建立保护性免疫至关重要，主要是通过将效应细胞因子干扰素-γ (IFN-γ) 传递给弓形虫感染的细胞。然而，目前尚不清楚记忆 CD8+ T 细胞如何响应弓形虫感染而发育，以及白细胞介素 12 (IL-12) 等炎性细胞因子在记忆发育中发挥多大作用。此外，诱导 CD8+ T 细胞活化的天然弓形虫抗原尚未完全被发现。利用新技术筛选抗原特异性，我们在 C57BL/6 小鼠中发现了弓形虫感染诱导的第一个天然抗原特异性 CD8+ T 细胞群。通过追踪天然寄生虫特异性反应，我们发现 IL-12 在促进产生 IFN-γ 的效应记忆 CD8+ T 细胞的发育中发挥着至关重要的作用，但代价是中央记忆 CD8+ T 细胞的数量和功能。
Production of the pro-inflammatory cytokine IL-12 by innate phagocytes drives the differentiation of IFN-γ-producing effector T cells during Toxoplasma gondii infection. However, the role of IL-12 in the regulation of memory CD8+ T cell differentiation and function during murine toxoplasmosis is unclear. To track memory CTL development, we identified a novel H-2Kb-restricted CTL population specific for the Toxoplasma antigen tgd057. Tgd057-specific CTLs were induced by both vaccination and natural peroral infection, and were representative of the polyclonal CTL population. Tgd057-specific primary effector cells required IL-12 for the differentiation of KLRG1+ effector subpopulations and IFN-γ production in response to restimulation with parasite-infected cells, but not to restimulation with cognate peptide. The effect of IL-12 deficiency during the primary response was profoundly imprinted on memory CTLs, which continued to show defects in cell numbers, KLRG1+ effector memory subpopulation differentiation, and IFN-γ recall responses. Importantly, isolated CD62Lhi KLRG1- CD8+ T cells differentiated in the absence of IL-12 were enhanced in their ability to generate IFN-γ-producing secondary tgd057-specific effector cells. Our data, for the first time, demonstrate the negative impact of IL-12 signaling on the quality of the central memory CTL compartment. Thus, despite the beneficial role of IL-12 in promoting effector differentiation, excessive exposure to IL-12 during CTL priming may limit the development of long-term protective immunity through the decreased fitness of central memory CTL responses. Toxoplasma gondii is a ubiquitous protozoan parasite that causes severe disease in people with compromised immune function. It is known that CD8+ T cells are essential for the establishment of protective immunity, primarily through the delivery of the effector cytokine interferon-γ (IFN-γ) to Toxoplasma-infected cells. However, it remains unclear how memory CD8+ T cells develop in response to Toxoplasma infection, and to what extent inflammatory cytokines like interleukin-12 (IL-12) play a role in memory development. Furthermore, the natural T. gondii antigens that induce CD8+ T cell activation have not yet been fully uncovered. Using new technology for the screening of antigen specificity, we discovered the first natural antigen-specific CD8+ T cell population induced by T. gondii infection in C57BL/6 mice. By tracking natural parasite-specific responses, we found that IL-12 plays a vital role in promoting the development of IFN-γ-producing effector memory CD8+ T cells but at a cost to the numbers and function of central memory CD8+ T cells.
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影响因子：
30.5
作者：
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通讯作者：
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真核生物寄生虫弓形虫的分泌流量：更少。
DOI：
10.1083/jcb.200112144
发表时间：
2002-05-13
期刊：
The Journal of cell biology
影响因子：
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作者：
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