Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar, India.
Front Immunol. 2018 May 28;9:1041. doi: 10.3389/fimmu.2018.01041. eCollection 2018.
The lethality of blood stage (PbA) infection is associated with the expression of T-bet and production of cytokine IFN-γ. Expression of inducible costimulator (ICOS) and its downstream signaling has been shown to play a critical role in the T-bet expression and IFN-γ production. Although earlier studies have examined the role of ICOS in the control of acute blood-stage infection of AS (a non-lethal model of malaria infection), its significance in the lethal blood-stage of PbA infection remains unclear. Thus, to address the seminal role of ICOS in lethal blood-stage of PbA infection, we treated PbA-infected mice with anti-ICOS antibody and observed that these mice survived longer than their infected counterparts with significantly lower parasitemia. Anti-ICOS treatment notably depleted ICOS expressing CD4 and CD8 T cells with a concurrent reduction in plasma IFN-γ, which strongly indicated that ICOS expressing T cells are major IFN-γ producers. Interestingly, we observed that while ICOS expressing CD4 and CD8 T cells produced IFN-γ, ICOSCD8 T cells were also found to be producers of IFN-γ. However, we report that ICOSCD8 T cells were higher producers of IFN-γ than ICOSCD8 T cells. Moreover, correlation of ICOS expression with IFN-γ production in ICOSIFN-γ T cell population (CD4 and CD8 T cells) suggested that ICOS and IFN-γ could positively regulate each other. Further, master transcription factor T-bet importantly involved in regulating IFN-γ production was also found to be expressed by ICOS expressing CD4 and CD8 T cells during PbA infection. As noted above with IFN-γ and ICOS, a positive correlation of expression of ICOS with the transcription factor T-bet suggested that both of them could regulate each other. Taken together, our results depicted the importance of ICOS expressing CD4 and CD8 T cells in malaria parasite growth and lethality through IFN-γ production and T-bet expression.
红内期（PbA）感染的致死性与 T 细胞激活标志物（T-bet）的表达和细胞因子 IFN-γ 的产生有关。诱导共刺激分子（ICOS）及其下游信号转导已被证明在 T-bet 表达和 IFN-γ 产生中发挥关键作用。尽管早期的研究已经检查了 ICOS 在控制急性血期感染的作用（一种非致死性疟疾感染模型），但其在致死性 PbA 感染中的意义仍不清楚。因此，为了确定 ICOS 在致死性 PbA 感染的红内期中的重要作用，我们用抗 ICOS 抗体治疗 PbA 感染的小鼠，观察到这些小鼠比感染的对照小鼠存活时间更长，寄生虫血症明显降低。抗 ICOS 治疗显著耗尽了表达 ICOS 的 CD4 和 CD8 T 细胞，同时减少了血浆 IFN-γ，这强烈表明表达 ICOS 的 T 细胞是 IFN-γ 的主要产生者。有趣的是，我们观察到，虽然表达 ICOS 的 CD4 和 CD8 T 细胞产生 IFN-γ，但也发现 ICOS+CD8 T 细胞是 IFN-γ的产生者。然而，我们报告说，ICOS+CD8 T 细胞比 ICOS+CD8 T 细胞产生更高水平的 IFN-γ。此外，在 ICOS+IFN-γ T 细胞群体（CD4 和 CD8 T 细胞）中，ICOS 表达与 IFN-γ 产生的相关性表明 ICOS 和 IFN-γ 可以相互正向调节。此外，在 PbA 感染期间，重要的调节 IFN-γ产生的主转录因子 T-bet 也被发现由表达 ICOS 的 CD4 和 CD8 T 细胞表达。如上所述，与 IFN-γ 和 ICOS 一样，ICOS 表达与转录因子 T-bet 的表达呈正相关，表明它们可以相互调节。总之，我们的研究结果表明，在疟原虫生长和致死性方面，表达 ICOS 的 CD4 和 CD8 T 细胞通过 IFN-γ 产生和 T-bet 表达发挥重要作用。
