美国科罗拉多大学Paul J. Norman等研究人员合作发现，古老的HLA I类受体等位基因在大洋洲第一民族人群中多样化自然杀伤细胞驱动的免疫反应。相关论文于2024年10月29日在线发表在《细胞》杂志上。
研究人员表示，宿主免疫中的遗传变异影响了第一民族人群所经历的传染病不成比例负担。多态性的人类白细胞抗原（HLA）I类和杀手细胞免疫球蛋白样受体（KIR）是自然杀伤（NK）细胞的关键调节因子，后者介导早期感染控制。然而，这种变异如何影响不同人群的反应尚不清楚。
研究人员发现，HLA-A24:02通过积极自然选择成为大洋洲第一民族人群中抑制性KIR3DL1的主要配体。研究人员鉴定出KIR3DL1114，这一等位基因在大洋洲广泛分布且独特，来源于古人类。来自第一民族澳大利亚供体的KIR3DL1114+ NK细胞通过与HLA-A24:02结合而被抑制。KIR3DL1*114谱系的特征是166位残基为苯丙氨酸。结构和结合研究表明，苯丙氨酸166与HLA-肽复合物形成多个独特接触，从而提高了亲和力和特异性。
因此，评估免疫遗传变异及其对免疫的功能影响，对于理解基于人群的疾病关联至关重要。
附：英文原文
Title: An archaic HLA class I receptor allele diversifies natural killer cell-driven immunity in First Nations peoples of Oceania
Author: Liyen Loh, Philippa M. Saunders, Camilla Faoro, Neus Font-Porterias, Neda Nemat-Gorgani, Genelle F. Harrison, Suraju Sadeeq, Luca Hensen, Shu Cheng Wong, Jacqueline Widjaja, E. Bridie Clemens, Shiying Zhu, Katherine M. Kichula, Sudan Tao, Faming Zhu, Gonzalo Montero-Martin, Marcelo Fernandez-Vina, Lisbeth A. Guethlein, Julian P. Vivian, Jane Davies, Alexander J. Mentzer, Stephen J. Oppenheimer, William Pomat, Alexander G. Ioannidis, Carmina Barberena-Jonas, Andrés Moreno-Estrada, Adrian Miller, Peter Parham, Jamie Rossjohn, Steven Y.C. Tong, Katherine Kedzierska, Andrew G. Brooks, Paul J. Norman
Issue&Volume: 2024-10-29
Abstract: Genetic variation in host immunity impacts the disproportionate burden of infectious diseases that can be experienced by First Nations peoples. Polymorphic human leukocyte antigen (HLA) class I and killer cell immunoglobulin-like receptors (KIRs) are key regulators of natural killer (NK) cells, which mediate early infection control. How this variation impacts their responses across populations is unclear. We show that HLA-A24:02 became the dominant ligand for inhibitory KIR3DL1 in First Nations peoples across Oceania, through positive natural selection. We identify KIR3DL1114, widespread across and unique to Oceania, as an allele lineage derived from archaic humans. KIR3DL1114+NK cells from First Nations Australian donors are inhibited through binding HLA-A24:02. The KIR3DL1114 lineage is defined by phenylalanine at residue 166. Structural and binding studies show phenylalanine 166 forms multiple unique contacts with HLA-peptide complexes, increasing both affinity and specificity. Accordingly, assessing immunogenetic variation and the functional implications for immunity are fundamental toward understanding population-based disease associations.
DOI: 10.1016/j.cell.2024.10.005
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01153-X