Wu Helen L, Wiseman Roger W, Hughes Colette M, Webb Gabriela M, Abdulhaqq Shaheed A, Bimber Benjamin N, Hammond Katherine B, Reed Jason S, Gao Lina, Burwitz Benjamin J, Greene Justin M, Ferrer Fidel, Legasse Alfred W, Axthelm Michael K, Park Byung S, Brackenridge Simon, Maness Nicholas J, McMichael Andrew J, Picker Louis J, O'Connor David H, Hansen Scott G, Sacha Jonah B
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006.
Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53706.
J Immunol. 2018 Jan 1;200(1):49-60. doi: 10.4049/jimmunol.1700841. Epub 2017 Nov 17.
MHC-E is a highly conserved nonclassical MHC class Ib molecule that predominantly binds and presents MHC class Ia leader sequence-derived peptides for NK cell regulation. However, MHC-E also binds pathogen-derived peptide Ags for presentation to CD8 T cells. Given this role in adaptive immunity and its highly monomorphic nature in the human population, HLA-E is an attractive target for novel vaccine and immunotherapeutic modalities. Development of HLA-E-targeted therapies will require a physiologically relevant animal model that recapitulates HLA-E-restricted T cell biology. In this study, we investigated MHC-E immunobiology in two common nonhuman primate species, Indian-origin rhesus macaques (RM) and Mauritian-origin cynomolgus macaques (MCM). Compared to humans and MCM, RM expressed a greater number of MHC-E alleles at both the population and individual level. Despite this difference, human, RM, and MCM MHC-E molecules were expressed at similar levels across immune cell subsets, equivalently upregulated by viral pathogens, and bound and presented identical peptides to CD8 T cells. Indeed, SIV-specific, Mamu-E-restricted CD8 T cells from RM recognized antigenic peptides presented by all MHC-E molecules tested, including cross-species recognition of human and MCM SIV-infected CD4 T cells. Thus, MHC-E is functionally conserved among humans, RM, and MCM, and both RM and MCM represent physiologically relevant animal models of HLA-E-restricted T cell immunobiology.
MHC-E是一种高度保守的非经典Ib类主要组织相容性复合体（MHC）分子，主要结合并呈递源自MHC Ia类前导序列的肽段以调节自然杀伤（NK）细胞。然而，MHC-E也结合病原体衍生的肽抗原以呈递给CD8 + T细胞。鉴于其在适应性免疫中的作用及其在人类群体中的高度单态性，HLA-E是新型疫苗和免疫治疗方法的一个有吸引力的靶点。开发针对HLA-E的疗法将需要一个能够概括HLA-E限制的T细胞生物学的生理相关动物模型。在本研究中，我们研究了两种常见的非人类灵长类动物物种——印度恒河猴（RM）和毛里求斯食蟹猴（MCM）中的MHC-E免疫生物学。与人类和MCM相比，RM在群体和个体水平上表达的MHC-E等位基因数量更多。尽管存在这种差异，但人类、RM和MCM的MHC-E分子在免疫细胞亚群中的表达水平相似，受到病毒病原体的上调程度相同，并且与CD8 + T细胞结合并呈递相同的肽段。事实上，来自RM的SIV特异性、受Mamu-E限制的CD8 + T细胞识别所有测试的MHC-E分子呈递的抗原肽，包括对人类和MCM的SIV感染的CD4 + T细胞的跨物种识别。因此，MHC-E在人类、RM和MCM中功能保守，并且RM和MCM都代表了HLA-E限制的T细胞免疫生物学的生理相关动物模型。
