Mucosal delivery of a respiratory syncytial virus CTL peptide with enterotoxin-based adjuvants elicits protective, immunopathogenic, and immunoregulatory antiviral CD8+ T cell responses
Mucosal delivery of a respiratory syncytial virus CTL peptide with enterotoxin-based adjuvants elicits protective, immunopathogenic, and immunoregulatory antiviral CD8+ T cell responses
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DOI：
10.4049/jimmunol.166.2.1106
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发表时间：
2001-01-15
影响因子：
4.4
通讯作者：
Dougan, G
中科院分区：
文献类型：
--
作者：
Simmons, CP;Hussell, T;Dougan, G
为了开发一种安全有效的呼吸道合胞病毒（RSV）疫苗，我们使用大肠杆菌不耐热毒素（LT）和LTK63（一种缺乏ADP-核糖基转移酶活性的LT突变体）来引发小鼠CD8（+）CTL对来自RSV第二基质蛋白（M2）的鼻内共递送CTL肽的反应。通过IFN-γ酶联免疫斑点和Cr-51释放测定在局部和全身淋巴结中检测M2（82-90）特异性CD8（+）T细胞，其诱导依赖于粘膜佐剂的使用。肽免疫引发的 CTL 提供了针对 RSV 攻击的保护，但也增强了体重减轻。 CTL 介导的病毒清除不依赖于 IFN-γ，因为在 RSV 攻击期间使用特定 mAb 进行清除不会影响细胞募集或病毒清除。然而，IFN-γ的消耗确实降低了受攻击小鼠肺匀浆中检测到的 TNF 浓度，并在很大程度上阻止了与 CTL 介导的病毒清除相关的体重减轻。经鼻内 RSV 攻击后，用附着糖蛋白 (G) 引发的小鼠会出现肺嗜酸粒细胞增多症。粘膜肽疫苗接种减少了随后用 G 免疫并用 RSV 攻击的泥沼中的肺嗜酸性粒细胞增多。这些研究强调，使用基于肠毒素的粘膜佐剂可以在粘膜上引发保护性和免疫调节性CD8+CTL反应，但对病毒感染的抵抗力可能伴随着疾病的增强。
In an effort to develop a safe and effective vaccine against respiratory syncytial virus (RSV), we used Escherichia coli heat-labile toxin (LT), and LTK63 (an LT mutant devoid of ADP-ribosyltransferase activity) to elicit murine CD8(+) CTL responses to an intranasally codelivered CTL peptide from the second matrix protein (M2) of RSV. M2(82-90)-specific CD8(+) T cells were detected by IFN-gamma enzyme-linked immunospot and Cr-51 release assay in local and systemic lymph nodes, and their induction was dependent on the use of a mucosal adjuvant. CTL elicited by peptide immunization afforded protection against RSV challenge, but also enhanced weight loss. CTL-mediated viral clearance was not dependent on IFN-gamma since depletion using specific mAb during RSV challenge did not affect cellular recruitment or viral clearance. Depletion of IFN-gamma did, however, reduce the concentration of TNF detected in lung homogenates of challenged mice and largely prevented the weight loss associated with CTL-mediated viral clearance. Mice primed with the attachment glycoprotein (G) develop lung eosinophilia after intranasal RSV challenge. Mucosal peptide vaccination reduced pulmonary eosinophilia in mire subsequently immunized with G and challenged with RSV. These studies emphasize that protective and immunoregulatory CD8(+) CTL responses can be mucosally elicited using enterotoxin-based mucosal adjuvants but that resistance against viral infection may be accompanied by enhanced disease.