The expanding number of rare immunodeficiency syndromes offers an opportunity to understand key genes that support immune defence against infectious diseases. However, analysis of these in patients is complicated by their treatments and co-morbid infections requiring the use of mouse models for detailed investigations. Here we develop a mouse model of DOCK2 immunodeficiency and demonstrate that these mice have delayed clearance of herpes simplex virus type 1 (HSV-1) infections. We also uncovered a critical, cell intrinsic role of DOCK2 in the priming of anti-viral CD8+ T cells and in particular their initial expansion, despite apparently normal early activation of these cells. When this defect was overcome by priming in vitro, DOCK2-deficient CD8+ T cells were surprisingly protective against HSV-1-disease, albeit not as effectively as wild type cells. These results shed light on a cellular deficiency that is likely to impact anti-viral immunity in DOCK2-deficient patients.

中文翻译：

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DOCK2缺陷会导致抗病毒T细胞反应缺陷并削弱对单纯疱疹病毒感染的控制

罕见免疫缺陷综合征数量的不断增加为了解支持传染病免疫防御的关键基因提供了机会。然而，对患者的这些分析由于他们的治疗和共病感染而变得复杂，需要使用小鼠模型进行详细研究。在这里，我们开发了 DOCK2 免疫缺陷小鼠模型，并证明这些小鼠对 1 型单纯疱疹病毒 (HSV-1) 感染的清除延迟。我们还发现了 DOCK2 在抗病毒 CD8+ T 细胞的启动，特别是它们的初始扩增中的关键细胞内在作用，尽管这些细胞的早期激活显然是正常的。当通过体外启动克服这一缺陷时，DOCK2 缺陷型 CD8+ T 细胞令人惊讶地对 HSV-1 疾病具有保护作用，尽管不如野生型细胞有效。这些结果揭示了细胞缺陷可能会影响 DOCK2 缺陷患者的抗病毒免疫力。