Randall Katrina L, Flesch Inge E A, Mei Yan, Miosge Lisa A, Aye Racheal, Yu Zhijia, Domaschenz Heather, Hollett Natasha A, Russell Tiffany A, Stefanovic Tijana, Wong Yik Chun, Goodnow Christopher C, Bertram Edward M, Enders Anselm, Tscharke David C
Division of Immunology and Infectious Diseases, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601.
School of Medicine and Psychology, Australian National University, Canberra ACT 2600.
bioRxiv. 2023 Aug 3:2023.08.02.551154. doi: 10.1101/2023.08.02.551154.
The expanding number of rare immunodeficiency syndromes offers an opportunity to understand key genes that support immune defence against infectious diseases. However, patients with these diseases are by definition rare. In addition, any analysis is complicated by 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. Further, we found that they have a critical, cell intrinsic role of DOCK2 in the clonal expansion of anti-viral CD8 T cells despite normal early activation of these cells. Finally, while the major deficiency is in clonal expansion, the ability of primed and expanded DOCK2-deficient CD8 T cells to protect against HSV-1-infection is also compromised. These results provide a contributing cause for the frequent and devastating viral infections seen in DOCK2-deficient patients and improve our understanding of anti-viral CD8 T cell immunity.
越来越多的罕见免疫缺陷综合征为了解支持免疫防御传染病的关键基因提供了契机。然而，从定义上讲，患有这些疾病的患者很罕见。此外，任何分析都因治疗和合并感染而变得复杂，这需要使用小鼠模型进行详细研究。在此，我们构建了DOCK2免疫缺陷小鼠模型，并证明这些小鼠清除1型单纯疱疹病毒（HSV-1）感染的能力延迟。此外，我们发现尽管抗病毒CD8 T细胞早期激活正常，但DOCK2在这些细胞的克隆扩增中具有关键的细胞内在作用。最后，虽然主要缺陷在于克隆扩增，但致敏并扩增的DOCK2缺陷型CD8 T细胞抵御HSV-1感染的能力也受到损害。这些结果为DOCK2缺陷患者中常见且严重的病毒感染提供了一个成因，并增进了我们对抗病毒CD8 T细胞免疫的理解。
