Plasmodium berghei Hsp90 contains a natural immunogenic I-A(b)-restricted antigen common to rodent and human Plasmodium species.
Plasmodium berghei Hsp90 contains a natural immunogenic I-A(b)-restricted antigen common to rodent and human Plasmodium species.
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DOI：
10.1016/j.crimmu.2021.06.002
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发表时间：
2021
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通过研究对特定特异性的反应，可以极大地帮助深入了解CD 4 T细胞在免疫中的作用。这需要疟原虫衍生的免疫原性表位的知识，其中只有少数已被确定，特别是对于小鼠C57 BL/6背景。我们最近开发了一个TCR转基因小鼠系，称为PbT-II，产生的CD 4 + T细胞特异性的MHC II类（I-Ab）限制的疟原虫表位，并响应于孢子和血液阶段伯氏疟原虫。在这里，我们确定了伯氏疟原虫热休克蛋白90内的肽作为PbT-II细胞识别的同源表位。我们发现感染伯氏疟原虫血液阶段的C57 BL/6小鼠诱导对该表位特异性的内源性CD 4 T细胞应答，表明与PbT-II细胞具有相似特异性的细胞存在于幼稚库中。连续转移体外活化的TH 1-或特别是TH 2-极化的PbT-II细胞改善了C57 BL/6小鼠中伯氏疟原虫寄生虫血症的控制，并显著降低了实验性脑型疟疾的发作。我们的研究结果确定了一个通用的，潜在的保护性MHC-II限制性表位，可用于探索CD 4 T细胞介导的免疫和疫苗接种策略，以对抗疟疾。伯氏疟原虫Hsp 90中新的MHC-II限制性表位的鉴定，其是PbT-II CD 4 + T细胞的同源抗原。该表位在小鼠疟原虫和引起人类疟疾的恶性疟原虫中是保守的。暴露于肝脏或血液阶段伯氏疟原虫感染扩增了内源性Hsp 90特异性CD 4 + T细胞的群体。树突状细胞靶向疫苗接种产生记忆PbT-II细胞和内源性Hsp 90特异性CD 4 + T细胞。TH 1-和TH 2-极化PbT-II细胞减少伯氏疟原虫寄生虫血症并减轻实验性脑型疟疾的发展。
Thorough understanding of the role of CD4 T cells in immunity can be greatly assisted by the study of responses to defined specificities. This requires knowledge of Plasmodium-derived immunogenic epitopes, of which only a few have been identified, especially for the mouse C57BL/6 background. We recently developed a TCR transgenic mouse line, termed PbT-II, that produces CD4+ T cells specific for an MHC class II (I-Ab)-restricted Plasmodium epitope and is responsive to both sporozoites and blood-stage P. berghei. Here, we identify a peptide within the P. berghei heat shock protein 90 as the cognate epitope recognised by PbT-II cells. We show that C57BL/6 mice infected with P. berghei blood-stage induce an endogenous CD4 T cell response specific for this epitope, indicating cells of similar specificity to PbT-II cells are present in the naïve repertoire. Adoptive transfer of in vitro activated TH1-, or particularly TH2-polarised PbT-II cells improved control of P. berghei parasitemia in C57BL/6 mice and drastically reduced the onset of experimental cerebral malaria. Our results identify a versatile, potentially protective MHC-II restricted epitope useful for exploration of CD4 T cell-mediated immunity and vaccination strategies against malaria. Identification of a novel MHC-II-restricted epitope in P. berghei Hsp90 that is the cognate antigen of PbT-II CD4+ T cells. This epitope is conserved among mouse malaria parasites and in Plasmodium falciparum, which causes human malaria. Exposure to liver or blood stage P. berghei infection expands a population of endogenous Hsp90-specific CD4+ T cells. Dendritic cell-targeted vaccination generates memory PbT-II cells and endogenous Hsp90-specific CD4+ T cells. TH1- and TH2-polarised PbT-II cells reduce P. berghei parasitaemia and mitigate development of experimental cerebral malaria.