Intradermal NKT cell activation during DNA priming in heterologous prime-boost vaccination enhances T cell responses and protection against Leishmania
Intradermal NKT cell activation during DNA priming in heterologous prime-boost vaccination enhances T cell responses and protection against Leishmania
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DOI：
10.1002/eji.200737660
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发表时间：
2008-03-01
影响因子：
5.4
通讯作者：
McMahon-Pratt, Diane
中科院分区：
文献类型：
--
作者：
Dondji, Blaise;Deak, Eszter;McMahon-Pratt, Diane
采用DNA-牛痘病毒（VACV）模式，使用利什曼原虫活化C激酶（LACK）（p36）抗原受体同源物进行异源性初免-加强免疫接种，已显示可引发针对鼠皮肤和内脏利什曼病的保护性免疫。然而，已知DNA引发具有有限的功效;因此，在当前研究中，检查了在皮内DNAp 36引发期间使用α-半乳糖神经酰胺（α GalCer）的NKT细胞活化的效果。接受aGalCer + DNAp 36随后用VVp 36加强的疫苗接种小鼠似乎正在解决它们的病变，并且寄生虫负荷降低了10至20倍。在aGalCer + DNAp 36引发期间的NKT细胞活化导致产生颗粒酶和IFN-γ的抗原反应性效应物CD 4（+）和CD 8（+）T细胞的数量更高，而IL-10的水平更低。尽管免疫耗竭研究表明，CD 4和CD 8 T细胞在接种疫苗的小鼠中提供保护，但在用DNAp 36与aGalCer一起致敏的小鼠中，CD 4（+）T细胞的贡献显著增加。值得注意的是，在加强后5个月，用DNAp 36 + aGalCer接种的小鼠继续显示持续和增强的T细胞免疫应答。因此，在初免期间使用α GalCer的异源初免-加强疫苗接种对鼠皮肤利什曼病具有高度保护性，导致CD 4和CD 8 T细胞（效应和记忆T细胞）的活化和发育增强。
Heterologous prime-boost vaccination employing DNA-vaccinia virus (VACV) modality using the Leishmania homologue of receptors for activated C kinase (LACK) (p36) antigen has been shown to elicit protective immunity against both murine cutaneous and visceral leishmaniasis. However, DNA priming is known to have limited efficacy; therefore in the current study the effect of NKT cell activation using alpha-galactosylceramide (alpha GalCer) during intradermal DNAp36 priming was examined. Vaccinated mice receiving alpha GalCer + DNAp36 followed by a boost with VVp36 appeared to be resolving their lesions and had at ten- to 20-fold higher reductions in parasite burdens. NKT cell activation during aGalCer + DNAp36 priming resulted in higher numbers of antigen-reactive effector CD4(+) and CD8(+) T cells producing granzyme and IFN-gamma, with lower levels of IL-10. Although immunodepletion studies indicate that both CD4 and CD8 T cells provide protection in the vaccinated mice, the contribution of CD4(+) T cells was significantly increased in mice primed with DNAp36 together with aGalCer. Notably 5 months after boosting, mice vaccinated with DNAp36 + alpha GalCer continued to show sustained and heightened T cell immune responses. Thus, heterologous prime-boost vaccination using alpha GalCer during priming is highly protective against murine cutaneous leishmaniasis, resulting in the heightened activation and development of CD4 and CD8 T cells (effector and memory T cells).