Reduced Plasmodium Parasite Burden Associates with CD38+ CD4+ T Cells Displaying Cytolytic Potential and Impaired IFN-γ Production.
Reduced Plasmodium Parasite Burden Associates with CD38+ CD4+ T Cells Displaying Cytolytic Potential and Impaired IFN-γ Production.
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DOI：
10.1371/journal.ppat.1005839
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发表时间：
2016-09
期刊：
影响因子：
6.7
通讯作者：
Doolan DL
中科院分区：
文献类型：
--
作者：
Burel JG;Apte SH;Groves PL;Klein K;McCarthy JS;Doolan DL
利用来自受控人类疟疾感染（CHMI）研究的独特样本资源，我们鉴定了一种新的CD 4 + T细胞群体，其在外周血中的频率与恶性疟原虫感染后的寄生虫负荷呈负相关。这些CD 4 + T细胞表达多功能胞外酶CD 38，并具有将其与其他CD 4 + T细胞区分开的独特特征。具体而言，它们的表型与增殖、活化和细胞毒性潜力以及IFN-γ和其他细胞因子的产生显著受损和活化的STAT 1的基础水平降低相关。在健康未感染个体中以较低的频率鉴定出具有相似特征的CD 38 + CD 4 + T细胞群体。CD 38-CD 4 + T细胞经抗原刺激或促有丝分裂刺激后，可在体外产生CD 38 + CD 4 + T细胞。这是第一次报告的人口的CD 38 + CD 4 + T细胞的细胞毒性表型和显着受损的IFN-γ的能力在人类。这种CD 38 + CD 4 + T细胞群在感染后的扩增及其与血液期寄生虫负荷减少的显著相关性与这些细胞在人类疟疾保护性免疫中的重要功能作用一致。它们在人类中的普遍存在表明它们可能在宿主-病原体防御中发挥广泛作用。ClinicalTrials.gov临床试验编号ACTRN 12612000814875、ACTRN 12613000565741和ACTRN 12613001040752疟疾是世界上三种最致命的传染病之一，另外两种是结核病和艾滋病毒。对疟疾有效免疫的确切机制在很大程度上仍然未知，也没有可靠的免疫保护相关性。在这里，我们利用一个独特的实验性人类感染模型，在分子水平上定义幼稚健康志愿者对血液期疟疾寄生虫初次暴露的免疫反应。我们报告说，疟原虫寄生虫水平呈负相关的CD 4 + T细胞表达的活化分子CD 38和一个非常不寻常的表型的一个特定的子集的扩展。虽然CD 38 + CD 4 + T细胞的扩增已经在几种病毒和细菌感染中描述，但我们首次表明这些细胞与“幼稚样”效应表型，更高的细胞溶解潜力和强烈受损的产生IFN-γ和其他细胞因子的能力相关。重要的是，在所有健康志愿者中也可以在感染前鉴定出这种CD 38 + CD 4 + T细胞亚群，这表明循环CD 38 + CD 4 + T细胞的这些核心特征与活动性感染无关，并且可能在其他病原体的免疫控制中发挥重要作用。
Using a unique resource of samples from a controlled human malaria infection (CHMI) study, we identified a novel population of CD4+ T cells whose frequency in the peripheral blood was inversely correlated with parasite burden following P. falciparum infection. These CD4+ T cells expressed the multifunctional ectoenzyme CD38 and had unique features that distinguished them from other CD4+ T cells. Specifically, their phenotype was associated with proliferation, activation and cytotoxic potential as well as significantly impaired production of IFN-γ and other cytokines and reduced basal levels of activated STAT1. A CD38+ CD4+ T cell population with similar features was identified in healthy uninfected individuals, at lower frequency. CD38+ CD4+ T cells could be generated in vitro from CD38- CD4+ T cells after antigenic or mitogenic stimulation. This is the first report of a population of CD38+ CD4+ T cells with a cytotoxic phenotype and markedly impaired IFN-γ capacity in humans. The expansion of this CD38+ CD4+ T population following infection and its significant association with reduced blood-stage parasite burden is consistent with an important functional role for these cells in protective immunity to malaria in humans. Their ubiquitous presence in humans suggests that they may have a broad role in host-pathogen defense. ClinicalTrials.gov clinical trial numbers ACTRN12612000814875, ACTRN12613000565741 and ACTRN12613001040752 Malaria is one of the three most deadly infectious disease worldwide, together with tuberculosis and HIV. The exact mechanisms underlying effective immunity to malaria remain largely unknown and there is no reliable immune correlate of protection. Here, we take advantage of a unique experimental human infection model to define the immune response to primary exposure of blood-stage malaria parasites in naïve healthy volunteers at the molecular level. We report that Plasmodium parasite levels were inversely correlated to the expansion of a specific subset of CD4+ T cells expressing the activation molecule CD38 and a very unusual phenotype. Although the expansion of CD38+ CD4+ T cells has been described in several viral and bacterial infections, we show for the first time that these cells are associated with a ‘naive-like’ effector phenotype, higher cytolytic potential and a strongly impaired ability to produce IFN-γ and other cytokines. Importantly, this subset of CD38+ CD4+ T cells could be also identified in all healthy volunteers prior to infection, suggesting that these core characteristics of circulating CD38+ CD4+ T cells are independent of active infection and may play an important role in the immune control of other pathogens.
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DOI：
10.4161/jkst.23504
发表时间：
2013-01-01
期刊：
JAK-STAT
影响因子：
--
作者：
Kallal LE;Biron CA
通讯作者：
Biron CA
影响因子：
4.4
作者：
Appay, V;Zaunders, JJ;Kelleher, AD
通讯作者：
Kelleher, AD
影响因子：
64.8
作者：
Kaplan, MH;Sun, YL;Grusby, MJ
通讯作者：
Grusby, MJ
影响因子：
5.4
作者：
Brown, Deborah M.;Lee, Sarah;Swain, Susan L.
通讯作者：
Swain, Susan L.
影响因子：
5.4
作者：
GROGG, D;HAHN, S;ERB, P
通讯作者：
ERB, P