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ICOS signaling promotes a secondary humoral response after re-challenge with Plasmodium chabaudi chabaudi AS.

ICOS信号转导在用疟原虫chabaudi chabaudi AS重新攻击后促进继发性体液反应。

  • 影响因子:6.02
  • DOI:10.1371/journal.ppat.1008527
  • 作者列表:"Latham LE","Wikenheiser DJ","Stumhofer JS
  • 发表时间:2020-04-29
Abstract

:The co-stimulatory molecule ICOS is associated with the induction and regulation of T helper cell responses, including the differentiation of follicular helper T (Tfh) cells and the formation and maintenance of memory T cells. However, the role of ICOS signaling in secondary immune responses is largely unexplored. Here we show that memory T cell formation and maintenance are influenced by persistent infection with P. chabaudi chabaudi AS infection, as memory T cell numbers decline in wild-type and Icos-/- mice after drug-clearance. Following drug-clearance Icos-/- mice display a relapsing parasitemia that occurs more frequently and with higher peaks compared to wild-type mice after re-challenge. The secondary immune response in Icos-/- mice is characterized by significant impairment in the expansion of effector cells with a Tfh-like phenotype, which is associated with a diminished and delayed parasite-specific Ab response and the absence of germinal centers. Similarly, the administration of an anti-ICOSL antagonizing antibody to wild-type mice before and after reinfection with P. c. chabaudi AS leads to an early defect in Tfh cell expansion and parasite-specific antibody production, confirming a need for ICOS-ICOSL interactions to promote memory B cell responses. Furthermore, adoptive transfer of central memory T (TCM) cells from wild-type and Icos-/- mice into tcrb-/- mice to directly evaluate the ability of TCM cells to give rise to Tfh cells revealed that TCM cells from wild-type mice acquire a mixed Th1- and Tfh-like phenotype after P. c. chabaudi AS infection. While TCM cells from Icos-/- mice expand and display markers of activation to a similar degree as their WT counterparts, they displayed a reduced capacity to upregulate markers indicative of a Tfh cell phenotype, resulting in a diminished humoral response. Together these findings verify that ICOS signaling in memory T cells plays an integral role in promoting T cell effector responses during secondary infection with P. c. chabaudi AS.

摘要

: 共刺激分子ICOS与T辅助细胞应答的诱导和调节相关,包括滤泡辅助T (Tfh) 细胞的分化以及记忆T细胞的形成和维持。然而,ICOS信号传导在次级免疫应答中的作用在很大程度上尚未探索。在这里,我们表明记忆T细胞的形成和维持受到感染P. chabaudi chabaudi的持续感染的影响,因为药物清除后野生型和Icos-/-小鼠的记忆T细胞数量下降。药物清除后,Icos-/-小鼠显示出复发的寄生虫血症,与再攻击后的野生型小鼠相比,其发生更频繁且具有更高的峰。Icos-/-小鼠中的次级免疫应答的特征在于具有Tfh样表型的效应细胞的扩增的显著损害,这与减少和延迟的寄生虫特异性Ab应答以及不存在生发中心有关。同样,在用P. c. chabaudi AS再感染之前和之后,给予野生型小鼠抗ICOSL拮抗抗体导致Tfh细胞扩增和寄生虫特异性抗体产生的早期缺陷,证实需要ICOS-ICOSL相互作用来促进记忆b细胞反应。此外,中枢记忆T (TCM) 的过继转移来自野生型和Icos-/-小鼠的细胞进入tcrb-/-小鼠以直接评估TCM细胞产生Tfh细胞的能力,揭示了来自野生型小鼠的TCM细胞在P后获得了混合的Th1和Tfh样表型。c. chabaudi作为感染。虽然来自Icos-/-小鼠的TCM细胞扩增并显示活化标志物至与其WT对应物相似的程度,但它们显示上调指示Tfh细胞表型的标志物的能力降低,导致体液反应减弱。这些发现一起验证了记忆T细胞中的ICOS信号在P. c. chabaudi AS的二次感染期间促进T细胞效应应答中起着不可或缺的作用。

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影响因子:0.85
发表时间:2020-01-02
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