Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
School of Medicine and Psychology, The Australian National University, Canberra, ACT, Australia.
J Infect Dis. 2024 Sep 23;230(3):e712-e721. doi: 10.1093/infdis/jiae077.
The expanding number of rare immunodeficiency syndromes offers an opportunity to understand key genes that support immune defense against infectious diseases. However, analysis of these in patients is complicated by their treatments and comorbid infections, requiring the use of mouse models for detailed investigations. We developed a mouse model of DOCK2 immunodeficiency and herein 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 antiviral 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 antiviral immunity in DOCK2-deficient patients.
不断增多的罕见免疫缺陷综合征为深入了解支持抗感染免疫的关键基因提供了机会。然而，这些疾病在患者中的分析受到其治疗和合并感染的影响，需要使用小鼠模型进行详细研究。我们建立了 DOCK2 免疫缺陷小鼠模型，并在此证明这些小鼠在单纯疱疹病毒 1（HSV-1）感染中的清除能力延迟。我们还揭示了 DOCK2 在抗病毒 CD8+T 细胞的初始激活和特别是其初始扩增中的关键的细胞内在作用，尽管这些细胞的早期激活似乎是正常的。当通过体外启动克服这一缺陷时，DOCK2 缺陷型 CD8+T 细胞对 HSV-1 疾病具有惊人的保护作用，尽管不如野生型细胞有效。这些结果揭示了一种可能影响 DOCK2 缺陷患者抗病毒免疫的细胞缺陷。
