Protection by and maintenance of CD4 effector memory and effector T cell subsets in persistent malaria infection.
Protection by and maintenance of CD4 effector memory and effector T cell subsets in persistent malaria infection.
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DOI：
10.1371/journal.ppat.1006960
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发表时间：
2018-04
期刊：
影响因子：
6.7
通讯作者：
Stephens R
中科院分区：
文献类型：
--
作者：
Opata MM;Ibitokou SA;Carpio VH;Marshall KM;Dillon BE;Carl JC;Wilson KD;Arcari CM;Stephens R
在夏氏疟原虫血液期疟疾感染高峰期的保护作用由CD 4 T细胞提供。我们已经表明，在疟疾的持续阶段，Th 1细胞的增加也与保护相关;然而，目前还不清楚这些T细胞是如何维持的。持续的疟疾感染促进保护并产生效应T细胞（Teff）和效应记忆T细胞（Tem）。我们之前定义了从早期（TeffEarly，CD 62 LhiCD 27+）到晚期（TeffLate，CD 62 LloCD 27-）激活状态的新CD 4 Teff（IL-7 R α-）亚群。在这里，我们测试了这些效应和记忆T细胞亚群在体内存活和保护的能力。我们发现多克隆和夏氏疟原虫裂殖子表面蛋白-1（MSP-1）特异性B5 TCR转基因Tem比Teff更好地存活。令人惊讶的是，由于Tem与抗原持久性相关，Tem甚至在感染清除后也能很好地存活。如前所述，在T细胞收缩期间，可以产生Tem的TeffEarly也比未感染受体中的其他Teff子集更好地存活。这里确定的另外两个Tem存活机制是，低水平慢性感染通过驱动它们的增殖和通过从Tcm编程Tem的产生来促进Tem。在疟疾或其他持续性感染中，保护性CD 4 T细胞表型尚未精确确定。因此，我们测试了纯化的记忆（Teff）和Teff亚群在免疫功能低下的受体小鼠中对峰值病理和寄生虫血症的保护作用。值得注意的是，在T细胞（IL-7 R αhi）亚群中，只有TemLate（CD 62 LloCD 27-）降低了峰值寄生虫血症（19%），尽管主要的记忆亚群是TemEarly，但它没有保护作用。与此相反，所有的Teff亚群减少了一半以上的寄生虫血症高峰，成熟的Teff可以产生Tem，虽然less. In总结，我们已经阐明了四种机制的Tem维护，并确定了两个长寿的T细胞亚群（TemLate，TeffEarly），可能代表相关的保护或目标的长寿疫苗诱导的保护疟疾血液阶段。疟疾造成严重的死亡率，但目前的候选疫苗的效力和持续时间都很差，对疟疾的天然免疫力也是如此。辅助性T细胞（CD 4+）对预防疟疾至关重要，但目前尚不清楚哪种T细胞既具有保护性又具有持久性。在这里，我们探索了记忆T细胞在疟疾中的生存机制，以及它们保护免疫缺陷动物免受疟疾的能力。我们确定了记忆T细胞在慢性感染中维持的四种机制。我们还表明，高度活化的效应T细胞通常比记忆T细胞保护得更好，然而，效应T细胞的寿命较短，这表明了短期免疫的机制。总的来说，我们确定了两个保护性T细胞亚群是长寿的。不幸的是，保护的记忆T细胞亚群并不是自然感染产生的主要记忆T细胞群，这表明疟疾中免疫力低下的机制。我们的工作表明，诱导这两种T细胞亚群的疫苗可能会改善目前对疟疾感染和疾病的免疫力。
Protection at the peak of Plasmodium chabaudi blood-stage malaria infection is provided by CD4 T cells. We have shown that an increase in Th1 cells also correlates with protection during the persistent phase of malaria; however, it is unclear how these T cells are maintained. Persistent malaria infection promotes protection and generates both effector T cells (Teff), and effector memory T cells (Tem). We have previously defined new CD4 Teff (IL-7Rα-) subsets from Early (TeffEarly, CD62LhiCD27+) to Late (TeffLate, CD62LloCD27-) activation states. Here, we tested these effector and memory T cell subsets for their ability to survive and protect in vivo. We found that both polyclonal and P. chabaudi Merozoite Surface Protein-1 (MSP-1)-specific B5 TCR transgenic Tem survive better than Teff. Surprisingly, as Tem are associated with antigen persistence, Tem survive well even after clearance of infection. As previously shown during T cell contraction, TeffEarly, which can generate Tem, also survive better than other Teff subsets in uninfected recipients. Two other Tem survival mechanisms identified here are that low-level chronic infection promotes Tem both by driving their proliferation, and by programming production of Tem from Tcm. Protective CD4 T cell phenotypes have not been precisely determined in malaria, or other persistent infections. Therefore, we tested purified memory (Tmem) and Teff subsets in protection from peak pathology and parasitemia in immunocompromised recipient mice. Strikingly, among Tmem (IL-7Rαhi) subsets, only TemLate (CD62LloCD27-) reduced peak parasitemia (19%), though the dominant memory subset is TemEarly, which is not protective. In contrast, all Teff subsets reduced peak parasitemia by more than half, and mature Teff can generate Tem, though less. In summary, we have elucidated four mechanisms of Tem maintenance, and identified two long-lived T cell subsets (TemLate, TeffEarly) that may represent correlates of protection or a target for longer-lived vaccine-induced protection against malaria blood-stages. Malaria causes significant mortality but current vaccine candidates have poor efficacy and duration, as does natural immunity to malaria. T helper cells (CD4+) are essential to protection from malaria, but it is unknown what kinds of T cells would be both protective and long-lasting. Here, we explored the mechanisms of survival used by memory T cells in malaria, and their ability to protect immunodeficient animals from malaria. We identified four mechanisms by which memory T cells are maintained in chronic infection. We also showed that highly activated effector T cells protect better than memory T cells in general, however, effector T cells have a shorter lifespan suggesting a mechanism for short-lived immunity. In total, we identified two protective T cell subsets that are long-lived. Unfortunately, the memory T cell subset that protects, is not the predominant memory T cell population generated by natural infection, suggesting a mechanism for the poor immunity seen in malaria. Our work suggests that vaccines that induce these two T cell subsets may improve on current immunity from malaria infection and disease.
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影响因子：
15.3
作者：
Macallan, DC;Wallace, D;Zhang, Y;de Lara, C;Worth, AT;Ghattas, H;Griffin, GE;Beverley, PCL;Tough, DE
通讯作者：
Tough, DE
激活表型，而不是中心或效应子内存表型，可预测记忆CD8+ T细胞的回忆功效。
影响因子：
15.3
作者：
Hikono, Hirokazu;Kohlmeier, Jacob E.;Takamura, Shiki;Wittmer, Susan T.;Roberts, Alan D.;Woodland, David L.
通讯作者：
Woodland, David L.
影响因子：
6.7
作者：
Peters NC;Pagán AJ;Lawyer PG;Hand TW;Henrique Roma E;Stamper LW;Romano A;Sacks DL
通讯作者：
Sacks DL
影响因子：
3.1
作者：
Li, C;Corraliza, I;Langhorne, J
通讯作者：
Langhorne, J
影响因子：
30.5
作者：
Intlekofer, AM;Takemoto, N;Reiner, SL
通讯作者：
Reiner, SL