Age-Dependent Cell Trafficking Defects in Draining Lymph Nodes Impair Adaptive Immunity and Control of West Nile Virus Infection.
Age-Dependent Cell Trafficking Defects in Draining Lymph Nodes Impair Adaptive Immunity and Control of West Nile Virus Infection.
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DOI：
10.1371/journal.ppat.1005027
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发表时间：
2015-07
期刊：
影响因子：
6.7
通讯作者：
Diamond MS
中科院分区：
文献类型：
--
作者：
Richner JM;Gmyrek GB;Govero J;Tu Y;van der Windt GJ;Metcalf TU;Haddad EK;Textor J;Miller MJ;Diamond MS
老年人的免疫反应受损会导致疫苗功效降低并增加对病毒感染的易感性。尽管一些研究小组已经记录了适应性免疫启动中与年龄相关的缺陷，但在抗原相遇之前发生的缺陷在很大程度上仍未得到探索。在此，我们确定了在感染西尼罗河病毒（WNV）的情况下随着衰老而发生的适应性免疫受损的新机制，西尼罗河病毒是一种脑炎黄病毒，优先在老年人中引起疾病。衰老过程中 IgM 和 IgG 反应受损以及对 WNV 感染的脆弱性增强与引流淋巴结 (DLN) 生发中心形成延迟有关。过继转移研究和双光子活体显微镜显示，来自年老小鼠的供体幼稚 CD4+ T 细胞的运输能力下降，表现为高内皮小静脉的 T 细胞渗出受损，以及在抗原遇到之前 DLN 内的细胞运动减少。此外，在老年小鼠中，在 WNV 感染或施用抗原佐剂的最初几天内，DLN 中的白细胞积累普遍减少，并且与局部细胞因子和趋化因子产生的第二个与衰老相关的缺陷有关。因此，DLN 中年龄依赖性细胞内在缺陷和环境缺陷导致免疫细胞招募和抗原识别延迟。这些缺陷会影响早期适应性免疫反应的启动，并可能导致年老动物对急性西尼罗河病毒感染的易感性。虽然西尼罗河病毒（WNV）感染优先在老年人中引起严重的神经侵袭性疾病，但这种流行病学联系的基础仍不确定。在这里，我们使用小鼠感染模型研究了衰老对西尼罗河病毒发病机制和免疫反应的影响。与成年小鼠相比，老年小鼠在感染西尼罗河病毒后表现出更高的致死率，这种表型与抗体反应延迟以及血液、脾脏和大脑中更高水平的病毒感染有关。详细的免疫学和显微镜分析揭示了引流淋巴结生发中心发育缺陷以及 WNV 感染后数天内幼稚 CD4+ T 细胞的迁移能力受损。这种缺陷因与年龄相关的几种趋化因子产生的单独缺陷而恶化，这些趋化因子将白细胞募集到发炎的淋巴结。因此，幼稚 CD4+ T 细胞运输和引流淋巴结环境中的年龄依赖性缺陷导致抗病毒反应延迟启动和无法控制 WNV，最终导致感染后死亡率升高。
Impaired immune responses in the elderly lead to reduced vaccine efficacy and increased susceptibility to viral infections. Although several groups have documented age-dependent defects in adaptive immune priming, the deficits that occur prior to antigen encounter remain largely unexplored. Herein, we identify novel mechanisms for compromised adaptive immunity that occurs with aging in the context of infection with West Nile virus (WNV), an encephalitic flavivirus that preferentially causes disease in the elderly. An impaired IgM and IgG response and enhanced vulnerability to WNV infection during aging was linked to delayed germinal center formation in the draining lymph node (DLN). Adoptive transfer studies and two-photon intravital microscopy revealed a decreased trafficking capacity of donor naïve CD4+ T cells from old mice, which manifested as impaired T cell diapedesis at high endothelial venules and reduced cell motility within DLN prior to antigen encounter. Furthermore, leukocyte accumulation in the DLN within the first few days of WNV infection or antigen-adjuvant administration was diminished more generally in old mice and associated with a second aging-related defect in local cytokine and chemokine production. Thus, age-dependent cell-intrinsic and environmental defects in the DLN result in delayed immune cell recruitment and antigen recognition. These deficits compromise priming of early adaptive immune responses and likely contribute to the susceptibility of old animals to acute WNV infection. While West Nile virus (WNV) infection preferentially causes severe neuroinvasive disease in elderly humans, the basis for this epidemiological linkage has remained uncertain. Here, we studied the impact of aging on WNV pathogenesis and immune responses using a mouse model of infection. Old mice showed increased lethality after WNV infection compared to adult mice, and this phenotype was associated with delayed antibody responses, and higher levels of virus infection in the blood, spleen, and brain. Detailed immunological and microscopic analyses revealed defects in germinal center development in the draining lymph node and impaired migratory capacity of naïve CD4+ T cells within days of WNV infection. This deficit was worsened by a separate age-related deficiency in the production of several chemokines that recruit leukocytes to inflamed lymph nodes. Thus, age-dependent defects in naïve CD4+ T cell trafficking and in the draining lymph node environment result in delayed initiation of antiviral responses and a failure to control WNV, which ultimately contributes to higher rates of mortality after infection.