IL-10 from CD4CD25Foxp3CD127 adaptive regulatory T cells modulates parasite clearance and pathology during malaria infection.
IL-10 from CD4CD25Foxp3CD127 adaptive regulatory T cells modulates parasite clearance and pathology during malaria infection.
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DOI：
10.1371/journal.ppat.1000004
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发表时间：
2008-02-29
期刊：
影响因子：
6.7
通讯作者：
Riley EM
中科院分区：
文献类型：
--
作者：
Couper KN;Blount DG;Wilson MS;Hafalla JC;Belkaid Y;Kamanaka M;Flavell RA;de Souza JB;Riley EM
疟疾感染的结果在一定程度上取决于促炎免疫反应和调节性免疫反应的平衡。未能形成有效的促炎反应可导致寄生虫的不受限制的复制，而未能调控这一反应会导致严重的免疫病理学的发展。已知IL-10和转化生长因子-β是调节反应的重要组成部分，但这些细胞因子的细胞来源尚不清楚。在这里，我们研究了自然和适应性调节性T细胞在控制疟疾感染中的作用，发现经典的CD4+CD25hi(和Foxp3+)调节性T细胞对感染致死(17XL)约氏疟原虫(PYL)株的结果没有显著影响。相反，我们发现在pYL和非致死性约氏疟原虫感染期间产生的适应性IL-10产生的CD_4+T细胞(CD25−、FOXP_3−和CD_(127)−，不产生Th1、Th2或Th17相关细胞因子)能够下调促炎反应并阻碍寄生虫清除。总之，我们已经确定了一组诱导的foxp3−调节(Tr1)T细胞，其特征是产生IL-10和下调IL-7Rα，调节疟疾的炎症反应。疟疾感染的大部分病理是由于对寄生虫的过度炎症反应。众所周知，调节性细胞因子IL-10可以控制疟疾感染期间的炎症，从而防止免疫病理，但在这样做的过程中，它会降低其他清除寄生虫的免疫机制的有效性。为了尝试分离IL-10的这两种作用，以便同时控制感染和避免病理，我们需要更好地了解导致IL-10产生的过程、产生的时间和产生它的细胞。在本研究中，我们发现约氏疟原虫感染过程中产生IL-10的主要来源是适应性调节的CD4+T细胞。这一群体有别于自然调节性T细胞和经典效应性T细胞。来自这些适应性CD4+T细胞的IL-10可以预防肝脏免疫病理，但也可以抑制效应器T细胞的反应，防止寄生虫清除。现在还需要进一步的工作来确定这两种关键细胞类型(抗寄生虫效应器T细胞和产生IL-10的调节性T细胞)是如何诱导的，以便设计出在感染的适当阶段诱导每种细胞类型的最佳数量的疫苗。
The outcome of malaria infection is determined, in part, by the balance of pro-inflammatory and regulatory immune responses. Failure to develop an effective pro-inflammatory response can lead to unrestricted parasite replication, whilst failure to regulate this response leads to the development of severe immunopathology. IL-10 and TGF-β are known to be important components of the regulatory response, but the cellular source of these cytokines is still unknown. Here we have examined the role of natural and adaptive regulatory T cells in the control of malaria infection and find that classical CD4+CD25hi (and Foxp3+) regulatory T cells do not significantly influence the outcome of infections with the lethal (17XL) strain of Plasmodium yoelii (PyL). In contrast, we find that adaptive IL-10-producing, CD4+ T cells (which are CD25−, Foxp3−, and CD127− and do not produce Th1, Th2, or Th17 associated cytokines) that are generated during both PyL and non-lethal P. yoelii 17X (PyNL) infections are able to down-regulate pro-inflammatory responses and impede parasite clearance. In summary, we have identified a population of induced Foxp3− regulatory (Tr1) T cells, characterised by production of IL-10 and down regulation of IL-7Rα, that modulates the inflammatory response to malaria. Much of the pathology of malaria infection is due to an excessive inflammatory response to the parasite. The regulatory cytokine IL-10 is known to control inflammation during malaria infections and thus protect against immunopathology, but, in so doing, it reduces the effectiveness of other immune mechanisms which remove the parasites. In order to try to dissociate these two effects of IL-10, to allow simultaneous control of infection and avoidance of pathology, we need a better understanding of the processes leading to IL-10 production, the timing of its production, and the cells that produce it. In this study we have found that the major source of IL-10 during malaria (Plasmodium yoelii) infection is adaptive regulatory CD4+ T cells. This population is distinct from natural regulatory T cells and classical effector T cells. IL-10 derived from these adaptive CD4+ T cells prevents hepatic immunopathology but also suppresses the effector T cell response, preventing parasite clearance. Further work is now required to determine how these two key cell types (anti-parasitic effector T cells and IL-10-producing regulatory T cells) are induced, so that vaccines can be designed that will induce optimal numbers of each cell type at appropriate stages of the infection.
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影响因子：
15.3
作者：
Fahlén, L;Read, S;Gorelik, L;Hurst, SD;Coffman, RL;Flavell, RA;Powrie, F
通讯作者：
Powrie, F
影响因子：
32.4
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29.4
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影响因子：
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作者：
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