IFN-γ and IL-21 Double Producing T Cells Are Bcl6-Independent and Survive into the Memory Phase in Plasmodium chabaudi Infection.
IFN-γ and IL-21 Double Producing T Cells Are Bcl6-Independent and Survive into the Memory Phase in Plasmodium chabaudi Infection.
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DOI：
10.1371/journal.pone.0144654
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Stephens R
中科院分区：
文献类型：
--
作者：
Carpio VH;Opata MM;Montañez ME;Banerjee PP;Dent AL;Stephens R
CD 4 T细胞通过促进吞噬活性和B细胞应答以清除寄生虫来对抗疟疾感染。在夏氏疟原虫感染中，一种特异性CD 4 T细胞亚群产生抗寄生虫IFN-γ和抗体促进细胞因子IL-21。为了确定这些多功能T细胞的谱系，我们使用Ifng报告小鼠跟踪IFN-γ+效应T细胞（Teff）进入记忆期。当Ifng + Teff扩增时，Th 1谱系决定转录因子T-bet的水平仅短暂达到峰值。Ifng + Teff还共表达ICOS、B细胞区域归巢分子CXCR 5和其它Tfh谱系相关分子，包括Bcl 6、生发中心（GC）T滤泡辅助细胞（Tfh）分化所需的转录因子。由于Bcl 6和T-bet共定位于Ifng + Teff的细胞核，我们假设Bcl 6控制了夏氏疟原虫感染中Ifng + Teff细胞的Tfh样表型。我们首先将Bcl 6缺陷型T细胞转移到野生型宿主中。Bcl 6缺陷型T细胞不发育成GC Tfh，但它们仍然产生CXCR 5 +IFN-γ+IL-21+IL-10+ Teff，表明该主要群体不是Tfh谱系。IFN-γ和T-bet表达增加的IL-10缺陷小鼠表现出IFN-γ+IL-21+ CXCR 5+细胞和IFN-γ+ GC Tfh细胞的扩增，表明前者的Th 1谱系。在记忆阶段，所有Ifng + T细胞产生IL-21，但只有一小部分高度增殖的Ifng + T细胞保持T-bethi表型。在慢性疟疾感染中，血清IFN-γ与增加的保护相关，并且我们的观察表明Ifng + T细胞通过细胞分裂维持。总之，我们发现Ifng + T细胞在疟疾感染期间不是严格的Tfh衍生的。T细胞在面对这种装备精良的病原体时为宿主提供了生存优势，因此，了解关键T细胞参与者的谱系将有助于合理设计有效的疟疾疫苗。
CD4 T cells are required to fight malaria infection by promoting both phagocytic activity and B cell responses for parasite clearance. In Plasmodium chabaudi infection, one specific CD4 T cell subset generates anti-parasitic IFN-γ and the antibody-promoting cytokine, IL-21. To determine the lineage of these multifunctional T cells, we followed IFN-γ+ effector T cells (Teff) into the memory phase using Ifng-reporter mice. While Ifng + Teff expanded, the level of the Th1 lineage-determining transcription factor T-bet only peaked briefly. Ifng + Teff also co-express ICOS, the B cell area homing molecule CXCR5, and other Tfh lineage-associated molecules including Bcl6, the transcription factor required for germinal center (GC) T follicular helper cells (Tfh) differentiation. Because Bcl6 and T-bet co-localize to the nucleus of Ifng + Teff, we hypothesized that Bcl6 controls the Tfh-like phenotype of Ifng + Teff cells in P. chabaudi infection. We first transferred Bcl6-deficient T cells into wildtype hosts. Bcl6-deficient T cells did not develop into GC Tfh, but they still generated CXCR5+IFN-γ+IL-21+IL-10+ Teff, suggesting that this predominant population is not of the Tfh-lineage. IL-10 deficient mice, which have increased IFN-γ and T-bet expression, demonstrated expansion of both IFN-γ+IL-21+CXCR5+ cells and IFN-γ+ GC Tfh cells, suggesting a Th1 lineage for the former. In the memory phase, all Ifng + T cells produced IL-21, but only a small percentage of highly proliferative Ifng + T cells maintained a T-bethi phenotype. In chronic malaria infection, serum IFN-γ correlates with increased protection, and our observation suggests Ifng + T cells are maintained by cellular division. In summary, we found that Ifng + T cells are not strictly Tfh derived during malaria infection. T cells provide the host with a survival advantage when facing this well-equipped pathogen, therefore, understanding the lineage of pivotal T cell players will aid in the rational design of an effective malaria vaccine.