Galectin-9/TIM-3 interaction regulates virus-specific primary and memory CD8 T cell response.
Galectin-9/TIM-3 interaction regulates virus-specific primary and memory CD8 T cell response.
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DOI：
10.1371/journal.ppat.1000882
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发表时间：
2010-05-06
期刊：
影响因子：
6.7
通讯作者：
Rouse BT
中科院分区：
文献类型：
--
作者：
Sehrawat S;Reddy PB;Rajasagi N;Suryawanshi A;Hirashima M;Rouse BT
在这次交流中，我们证明了半乳糖凝集素（Gal）-9的作用，以限制CD 8 + T细胞免疫单纯疱疹病毒（HSV）感染。为了支持这一点，我们表明，由于基因敲除，动物无法产生Gal-9，对HSV产生的急性和记忆反应比正常感染动物的反应更大，质量更好。有趣的是，用α-乳糖（结合Gal-9的碳水化合物结合结构域的糖，限制其与T细胞免疫球蛋白和粘蛋白（TIM-3）受体的结合）输注正常感染的小鼠，也引起了对HSV的更高和更高质量的CD 8 + T细胞应答，特别是在急性期。这种糖处理的感染小鼠也具有扩增的效应和记忆CD 8 + T细胞群体。增加的效应T细胞应答导致显著更有效的病毒控制。负责正常感染小鼠中Gal-9/TIM-3相互作用结果的机制涉及对TIM-3+ CD 8 + T效应细胞的直接抑制作用以及Foxp 3+调节性T细胞活性的促进。我们的研究结果表明，操纵半乳糖凝集素信号，可以实现使用适当的糖，可能是一种方便和廉价的方法，以提高急性和记忆反应的病毒感染。对外来抗原的适应性免疫应答需要精确的调节，否则可能发生对宿主组织的过度旁观者损伤，并且可能损害对其他抗原的应答。一些半乳糖凝集素蛋白结合到免疫系统细胞上的受体上，形成调节系统的一部分，尽管这一主题由于与抗病毒控制有关而很少受到关注。在这份报告中，我们评估了半乳糖凝集素-9/TIM-3受体途径在调节急性和记忆性CD 8 + T细胞对单纯疱疹病毒（HSV）感染的反应中的作用。我们证明，与野生型对照相比，由于基因敲除而不能产生半乳糖凝集素-9的小鼠中，对HSV的CD 8 + T细胞应答在幅度上显著增加，并且在质量上得到改善。此外，使用与Gal-9结合的糖α-乳糖抑制半乳糖凝集素-9介导的对TIM-3的应答导致类似的应答模式。半乳糖凝集素-9对抑制CD 8 + T细胞应答的影响涉及对T效应子的直接抑制作用以及对调节性T细胞应答的促进。我们的研究结果表明，使用单糖操纵半乳糖凝集素与受体的相互作用可能代表了一种方便且廉价的方法来增强T细胞对病毒感染的反应，并可能被证明有助于提高某些疫苗的效力。
In this communication, we demonstrate that galectin (Gal)-9 acts to constrain CD8+ T cell immunity to Herpes Simplex Virus (HSV) infection. In support of this, we show that animals unable to produce Gal-9, because of gene knockout, develop acute and memory responses to HSV that are of greater magnitude and better quality than those that occur in normal infected animals. Interestingly, infusion of normal infected mice with α-lactose, the sugar that binds to the carbohydrate-binding domain of Gal-9 limiting its engagement of T cell immunoglobulin and mucin (TIM-3) receptors, also caused a more elevated and higher quality CD8+ T cell response to HSV particularly in the acute phase. Such sugar treated infected mice also had expanded populations of effector as well as memory CD8+ T cells. The increased effector T cell responses led to significantly more efficient virus control. The mechanisms responsible for the outcome of the Gal-9/TIM-3 interaction in normal infected mice involved direct inhibitory effects on TIM-3+ CD8+ T effector cells as well as the promotion of Foxp3+ regulatory T cell activity. Our results indicate that manipulating galectin signals, as can be achieved using appropriate sugars, may represent a convenient and inexpensive approach to enhance acute and memory responses to a virus infection. Adaptive immune responses to foreign antigens require precise regulation, otherwise excessive bystander damage to host tissues may occur and responses to other antigens could be compromised. Some galectin proteins binding to receptors on cells of the immune system form part of the regulatory system, although this topic has received scant attention as it relates to antiviral control. In this report, we evaluate the role of the galectin-9/TIM-3 receptor pathway at regulating acute and memory CD8+ T cell responses to herpes simplex virus (HSV) infection. We demonstrate that CD8+ T cell responses to HSV were significantly increased in magnitude and improved in quality in mice unable to produce galectin-9 because of gene knockout compared to wild type controls. Furthermore, inhibiting the galectin-9 mediated response to TIM-3 using the sugar alpha-lactose that binds to Gal-9 led to a similar response pattern. The influence of galectin-9 to constrain CD8+ T cell responses involved direct inhibitory effects on the T effectors as well as the promotion of regulatory T cell responses. Our results indicate that manipulating the interaction of galectins with receptors using simple sugars may represent a convenient and inexpensive approach to enhance T cell responses to virus infections, and could prove useful to increase the efficacy of some vaccines.
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