KG Jebsen Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, 0372 Oslo, Norway.
Department of Immunology, Oslo University Hospital-Rikshospitalet, 0372 Oslo, Norway; and.
Immunohorizons. 2021 Jan 18;5(1):25-32. doi: 10.4049/immunohorizons.2000107.
The human MHC class II molecule HLA-DQ2.5 is implicated in multiple autoimmune disorders, including celiac disease, type 1 diabetes, and systemic lupus erythematosus. The pathogenic contribution of HLA-DQ2.5 in many of these disorders is not fully understood. There is thus a need for an HLA-DQ2.5 humanized mouse model with physiological expression of this MHC molecule that can be integrated into disease models. In this article, we report the generation of an HLA-DQ2.5 knock-in mouse strain on a C57BL/6 background in which sequences encoding the extracellular moieties of mouse MHC class II and have been replaced with those of and In heterozygous knock-in mice, the expression of HLA-DQ2.5 is superimposable with the expression of H2-IA. This was not the case in a regular untargeted HLA-DQ2.5 transgenic mouse. HLA-DQ2.5 in the knock-in animals is functional for T cell development and for Ag presentation to HLA-DQ2.5-restricted and gluten-specific T cells. Because C57BL/6 mice do not express , the only functional MHC class II molecule in homozygous HLA-DQ2.5 knock-in mice is the knock-in gene product. This alleviates the need for crossing with MHC class II knockout mice to study the isolated function of the MHC transgene. Our novel mouse strain provides an important tool to study the involvement of HLA-DQ2.5 in models of diseases with association to this HLA allotype.
人类 MHC Ⅱ类分子 HLA-DQ2.5 与多种自身免疫性疾病有关，包括乳糜泻、1 型糖尿病和系统性红斑狼疮。在许多这些疾病中，HLA-DQ2.5 的致病作用尚未完全阐明。因此，需要有一种具有这种 MHC 分子生理表达的 HLA-DQ2.5 人源化小鼠模型，可以将其整合到疾病模型中。在本文中，我们报告了在 C57BL/6 背景下生成 HLA-DQ2.5 敲入小鼠品系的情况，其中编码小鼠 MHC Ⅱ类和 的细胞外部分的序列已被 和 的序列所取代。在杂合敲入小鼠中，HLA-DQ2.5 的表达与 H2-IA 的表达重叠。在常规非靶向 HLA-DQ2.5 转基因小鼠中并非如此。在敲入动物中，HLA-DQ2.5 可用于 T 细胞发育，并可将抗原呈递给 HLA-DQ2.5 限制性和谷蛋白特异性 T 细胞。由于 C57BL/6 小鼠不表达 ，因此在纯合 HLA-DQ2.5 敲入小鼠中唯一功能性 MHC Ⅱ类分子是敲入基因产物。这减轻了与 MHC Ⅱ类敲除小鼠杂交以研究 MHC 转基因的单独功能的需要。我们的新型小鼠品系为研究 HLA-DQ2.5 在与这种 HLA 同种型相关的疾病模型中的作用提供了重要工具。
