Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4+ T Cell Immunity
Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4+ T Cell Immunity
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DOI：
10.1371/journal.ppat.1004085
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发表时间：
2014-05-01
期刊：
影响因子：
6.7
通讯作者：
Altmann, Daniel M.
中科院分区：
文献类型：
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作者：
Ascough, Stephanie;Ingram, Rebecca J.;Altmann, Daniel M.
炭疽杆菌产生一种二元毒素，由保护性抗原 (PA) 和致死因子 (LF) 或水肿因子 (EF) 两个亚基之一组成。大多数研究都集中在诱导毒素特异性抗体作为保护性免疫的相关性上，相比之下，对这些毒素的细胞免疫及其对感染的影响的理解是有限的。我们在一组人源化 HLA-DR 和 DQ 转基因小鼠以及自然暴露的患者中表征了 CD4(+) T 细胞对 LF 的免疫。由于 HLA 多态性控制的抗原呈递变化对特定表位的保护性免疫具有重大影响，因此我们检查了 LF 肽与纯化的 HLA II 类分子的相对结合亲和力，通过其结合多个等位基因的能力，识别出可能广泛适用于人类免疫研究的区域。转基因仅在人类 HLA II 类等位基因的表达上有所不同，表现出对 LF 的明显免疫等级。 HLA 转基因的免疫原性主要限于来自 LF 结构域 II 和 IV 的表位，并且在结构域 II 中鉴定出所有 HLA 类型共有的混杂的显性表位。该模型的相关性进一步证明了以下事实：在小鼠中鉴定的许多免疫显性表位被来自先前感染皮肤炭疽的人类和接种疫苗的个体的 T 细胞识别。通过对用包含我们鉴定的免疫显性表位的肽亚单位疫苗免疫的HLA转基因小鼠进行致死性炭疽攻击，证明了所鉴定的表位赋予保护性免疫的能力。
Bacillus anthracis produces a binary toxin composed of protective antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). Most studies have concentrated on induction of toxin-specific antibodies as the correlate of protective immunity, in contrast to which understanding of cellular immunity to these toxins and its impact on infection is limited. We characterized CD4(+) T cell immunity to LF in a panel of humanized HLA-DR and DQ transgenic mice and in naturally exposed patients. As the variation in antigen presentation governed by HLA polymorphism has a major impact on protective immunity to specific epitopes, we examined relative binding affinities of LF peptides to purified HLA class II molecules, identifying those regions likely to be of broad applicability to human immune studies through their ability to bind multiple alleles. Transgenics differing only in their expression of human HLA class II alleles showed a marked hierarchy of immunity to LF. Immunogenicity in HLA transgenics was primarily restricted to epitopes from domains II and IV of LF and promiscuous, dominant epitopes, common to all HLA types, were identified in domain II. The relevance of this model was further demonstrated by the fact that a number of the immunodominant epitopes identified in mice were recognized by T cells from humans previously infected with cutaneous anthrax and from vaccinated individuals. The ability of the identified epitopes to confer protective immunity was demonstrated by lethal anthrax challenge of HLA transgenic mice immunized with a peptide subunit vaccine comprising the immunodominant epitopes that we identified.