Medical Research Council Human Immunology Unit, Weatherall Institute for Molecular Medicine, Oxford University, John Radcliffe Hospital, Oxford, United Kingdom;
Blood. 2013 Sep 19;122(12):2052-61. doi: 10.1182/blood-2013-02-482331. Epub 2013 Aug 8.
Patients with the dedicator of cytokinesis 8 (DOCK8) immunodeficiency syndrome suffer from recurrent viral and bacterial infections, hyper-immunoglobulin E levels, eczema, and greater susceptibility to cancer. Because natural killer T (NKT) cells have been implicated in these diseases, we asked if these cells were affected by DOCK8 deficiency. Using a mouse model, we found that DOCK8 deficiency resulted in impaired NKT cell development, principally affecting the formation and survival of long-lived, differentiated NKT cells. In the thymus, DOCK8-deficient mice lack a terminally differentiated subset of NK1.1(+) NKT cells expressing the integrin CD103, whereas in the liver, DOCK8-deficient NKT cells express reduced levels of the prosurvival factor B-cell lymphoma 2 and the integrin lymphocyte function-associated antigen 1. Although the initial NKT cell response to antigen is intact in the absence of DOCK8, their ongoing proliferative and cytokine responses are impaired. Importantly, a similar defect in NKT cell numbers was detected in DOCK8-deficient humans, highlighting the relevance of the mouse model. In conclusion, our data demonstrate that DOCK8 is required for the development and survival of mature NKT cells, consistent with the idea that DOCK8 mediates survival signals within a specialized niche. Accordingly, impaired NKT cell numbers and function are likely to contribute to the susceptibility of DOCK8-deficient patients to recurrent infections and malignant disease.
患有胞分裂作用因子 8（DOCK8）免疫缺陷综合征的患者会遭受反复的病毒和细菌感染、高免疫球蛋白 E 水平、湿疹和更高的癌症易感性。由于自然杀伤 T（NKT）细胞与这些疾病有关，我们询问这些细胞是否受到 DOCK8 缺乏的影响。使用小鼠模型，我们发现 DOCK8 缺乏导致 NKT 细胞发育受损，主要影响长寿、分化的 NKT 细胞的形成和存活。在胸腺中，DOCK8 缺陷型小鼠缺乏表达整合素 CD103 的 NK1.1(+) NKT 细胞的终末分化亚群，而在肝脏中，DOCK8 缺陷型 NKT 细胞表达的生存因子 B 细胞淋巴瘤 2 和整合素淋巴细胞功能相关抗原 1 的水平降低。尽管在缺乏 DOCK8 的情况下，初始 NKT 细胞对抗原的反应是完整的，但它们的持续增殖和细胞因子反应受损。重要的是，在 DOCK8 缺陷型人类中也检测到了 NKT 细胞数量的类似缺陷，突出了该小鼠模型的相关性。总之，我们的数据表明 DOCK8 是成熟 NKT 细胞发育和存活所必需的，这与 DOCK8 在特定龛位中传递生存信号的观点一致。因此，NKT 细胞数量和功能的受损可能导致 DOCK8 缺陷患者易受反复感染和恶性疾病的影响。
