Resistance to chronic Toxoplasma gondii infection requires ongoing recruitment of T cells to the brain. Thus, the factors that promote, sustain, and regulate the T cell response to the parasite in the brain are of great interest. The costimulatory molecule ICOS (inducible T cell costimulator) has been reported to act largely through the PI3K pathway in T cells, and can play pro-inflammatory or pro-regulatory roles depending on the inflammatory context and T cell type being studied. During infection with T. gondii, ICOS promotes early T cell responses, while in the chronic stage of infection ICOS plays a regulatory role by limiting T cell responses in the brain. We sought to characterize the role of ICOS signaling through PI3K during chronic infection using two models of ICOS deficiency: total ICOS knockout (KO) mice and ICOS YF mice that are unable to activate PI3K signaling. Overall, ICOS KO and ICOS YF mice had similar severe defects in parasite-specific IgG production and parasite control compared to WT mice. Additionally, we observed expanded effector T cell populations and a loss of Treg frequency in the brains of both ICOS KO and ICOS YF mice. When comparing the remaining Treg populations in infected mice, ICOS KO Tregs expressed WT levels of Foxp3 and CD25, while ICOS YF Tregs expressed significantly less Foxp3 and CD25 compared to both WT and ICOS KO mice. Together, these results suggest that PI3K-independent signaling downstream of ICOS plays an important role in Treg stability in the context of chronic inflammation.

中文翻译：

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ICOS缺陷和ICOS YF突变小鼠无法控制弓形虫的脑部感染。

对弓形虫慢性感染的抗药性要求T细胞不断向大脑募集。因此，引起，维持和调节T细胞对脑中寄生虫的反应的因素引起了极大的兴趣。据报道，共刺激分子ICOS（诱导性T细胞共刺激物）主要通过T细胞中的PI3K途径起作用，并且可以根据炎症环境和所研究的T细胞类型发挥促炎或促调节作用。在弓形虫感染期间，ICOS促进早期T细胞反应，而在慢性感染阶段，ICOS通过限制大脑中的T细胞反应发挥调节作用。我们试图使用两种ICOS缺乏模型来表征在慢性感染期间通过PI3K进行ICOS信号传导的作用：不能激活PI3K信号转导的总ICOS基因敲除（KO）小鼠和ICOS YF小鼠。总体而言，与WT小鼠相比，ICOS KO和ICOS YF小鼠在寄生虫特异性IgG产生和寄生虫控制方面具有相似的严重缺陷。此外，我们在ICOS KO和ICOS YF小鼠的大脑中观察到了扩大的效应T细胞群和Treg频率的损失。当比较感染小鼠中其余的Treg种群时，与WT和ICOS KO小鼠相比，ICOS KO Tregs表达WT的Foxp3和CD25水平，而ICOS YF Tregs表达的Foxp3和CD25明显更少。总之，这些结果表明，在慢性炎症的情况下，ICOS下游不依赖PI3K的信号传导在Treg稳定性中起重要作用。与WT小鼠相比，ICOS KO和ICOS YF小鼠在寄生虫特异性IgG产生和寄生虫控制方面具有相似的严重缺陷。此外，我们在ICOS KO和ICOS YF小鼠的大脑中观察到了扩大的效应T细胞群和Treg频率的损失。当比较感染小鼠中其余的Treg种群时，与WT和ICOS KO小鼠相比，ICOS KO Tregs表达WT的Foxp3和CD25水平，而ICOS YF Tregs表达的Foxp3和CD25明显更少。总之，这些结果表明，在慢性炎症的情况下，ICOS下游不依赖PI3K的信号传导在Treg稳定性中起重要作用。与WT小鼠相比，ICOS KO和ICOS YF小鼠在寄生虫特异性IgG产生和寄生虫控制方面具有相似的严重缺陷。此外，我们在ICOS KO和ICOS YF小鼠的大脑中观察到了扩大的效应T细胞群和Treg频率的损失。当比较感染小鼠中其余的Treg种群时，与WT和ICOS KO小鼠相比，ICOS KO Tregs表达WT的Foxp3和CD25水平，而ICOS YF Tregs表达的Foxp3和CD25明显更少。总之，这些结果表明，在慢性炎症的情况下，ICOS下游不依赖PI3K的信号传导在Treg稳定性中起重要作用。当比较感染小鼠中其余的Treg种群时，与WT和ICOS KO小鼠相比，ICOS KO Tregs表达WT的Foxp3和CD25水平，而ICOS YF Tregs表达的Foxp3和CD25明显更少。总之，这些结果表明，在慢性炎症的情况下，ICOS下游不依赖PI3K的信号传导在Treg稳定性中起重要作用。当比较感染小鼠中其余的Treg种群时，与WT和ICOS KO小鼠相比，ICOS KO Tregs表达WT的Foxp3和CD25水平，而ICOS YF Tregs表达的Foxp3和CD25明显更少。总之，这些结果表明，在慢性炎症的情况下，ICOS下游不依赖PI3K的信号传导在Treg稳定性中起重要作用。