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首页> 外文期刊>Vaccine >Highly conserved pattern of recognition of influenza A wild-type and variant CD8+ CTL epitopes in HLA-A2+ humans and transgenic HLA-A2+/H2 class I-deficient mice
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Highly conserved pattern of recognition of influenza A wild-type and variant CD8+ CTL epitopes in HLA-A2+ humans and transgenic HLA-A2+/H2 class I-deficient mice

机译：在HLA-A2 +人类和转基因HLA-A2 + / H2 I类缺陷小鼠中识别A型流感野生型和变异CD8 + CTL表位的高度保守模式

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摘要

As an in vivo model for studying human MHC (HLA) class I-restricted CTL responses to viral infection, we established a series of HLA Tg mice expressing HLA-A2, -B7 or -B27 human/mouse hybrid genes on a background deficient for H2 class I (Tg HLA(hyb)/H2 class I DKO). To determine whether CTL recognition of influenza A (flu) infection in Tg HLA-A2(hyb)/H2 DKO mice is similar to HLA-A2+ humans, we compared the HLA-A2-restricted Tg mouse and human CD8+ T-cell responses to an immunodominant flu epitope (wild-type [WT] M1 58-66), as well as a variant of this peptide (var. M1 58-66). Similar to HLA-A2+ humans, our results show WT M1 58-66 is likely the dominant CTL epitope recognized in infected Tg HLA-A2(hyb)/H2 DKO mice. Var. M1 58-66 was also recognized by WT peptide-reactive T cells from both HLA-A2+ humans and Tg mice, although slightly less efficiently than WT M1 58-66 in both cases. Reduced variant recognition was shown to be associated with reduced peptide/A2 binding, as well as a more limited repertoire of utilized TCR Vbeta chains. The similar pattern of recognition and cross reaction observed here for the WT and variant M1 58-66 epitopes with HLA-A2 by human and Tg HLA mouse CTLs indicates that A2-dependent events of Ag processing, presentation and recognition are well-conserved between species. These findings demonstrate that this Tg HLA-A2/H2 DKO model will aid identification and development of epitopes as vaccines for numerous viral and tumor antigens for the HLA-A2 supertype.
机译：作为研究人类MHC（HLA）I类限制性CTL对病毒感染的反应的体内模型，我们建立了一系列HLA Tg小鼠，它们在缺乏以下基因的背景下表达HLA-A2，-B7或-B27人/小鼠杂交基因H2 I类（Tg HLA（hyb）/ H2 I DKO）。为了确定CTL对Tg HLA-A2（hyb）/ H2 DKO小鼠中的甲型流感（flu）感染的CTL识别是否类似于HLA-A2 +人类，我们将HLA-A2限制性Tg小鼠和人类CD8 + T细胞反应与免疫显性流感抗原决定簇（野生型[WT] M1 58-66），以及该肽的变体（变体M1 58-66）。与HLA-A2 +人类相似，我们的结果显示，WT M1 58-66可能是受感染的Tg HLA-A2（hyb）/ H2 DKO小鼠中公认的显性CTL表位。变体来自HLA-A2 +人和Tg小鼠的WT肽反应性T细胞也可识别M1 58-66，尽管在这两种情况下效率均略低于WT M1 58-66。已显示变体识别减少与肽/ A2结合减少以及所用TCR Vbeta链的库更为有限。在此处观察到的人类和Tg HLA小鼠CTL对WT和带有HLA-A2的M1 58-66变体表位的识别和交叉反应的相似模式表明，Ag加工，呈递和识别的A2依赖事件在物种之间保存良好。 。这些发现表明，该Tg HLA-A2 / H2 DKO模型将有助于鉴定和开发表位，作为针对HLA-A2超型的众多病毒和肿瘤抗原的疫苗。

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