Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
PLoS Biol. 2011 Nov;9(11):e1001187. doi: 10.1371/journal.pbio.1001187. Epub 2011 Nov 1.
X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency caused by mutations in SH2D1A which encodes SAP. SAP functions in signalling pathways elicited by the SLAM family of leukocyte receptors. A defining feature of XLP is exquisite sensitivity to infection with EBV, a B-lymphotropic virus, but not other viruses. Although previous studies have identified defects in lymphocytes from XLP patients, the unique role of SAP in controlling EBV infection remains unresolved. We describe a novel approach to this question using female XLP carriers who, due to random X-inactivation, contain both SAP(+) and SAP(-) cells. This represents the human equivalent of a mixed bone marrow chimera in mice. While memory CD8(+) T cells specific for CMV and influenza were distributed across SAP(+) and SAP(-) populations, EBV-specific cells were exclusively SAP(+). The preferential recruitment of SAP(+) cells by EBV reflected the tropism of EBV for B cells, and the requirement for SAP expression in CD8(+) T cells for them to respond to Ag-presentation by B cells, but not other cell types. The inability of SAP(-) clones to respond to Ag-presenting B cells was overcome by blocking the SLAM receptors NTB-A and 2B4, while ectopic expression of NTB-A on fibroblasts inhibited cytotoxicity of SAP(-) CD8(+) T cells, thereby demonstrating that SLAM receptors acquire inhibitory function in the absence of SAP. The innovative XLP carrier model allowed us to unravel the mechanisms underlying the unique susceptibility of XLP patients to EBV infection in the absence of a relevant animal model. We found that this reflected the nature of the Ag-presenting cell, rather than EBV itself. Our data also identified a pathological signalling pathway that could be targeted to treat patients with severe EBV infection. This system may allow the study of other human diseases where heterozygous gene expression from random X-chromosome inactivation can be exploited.
X 连锁淋巴组织增生性疾病（XLP）是一种由 SH2D1A 基因突变引起的原发性免疫缺陷病，该基因编码 SAP。SAP 在信号通路中发挥作用，这些信号通路是由白细胞受体 SLAM 家族引发的。XLP 的一个显著特征是对 EBV（一种 B 淋巴细胞嗜性病毒）感染极为敏感，但对其他病毒不敏感。尽管先前的研究已经确定了 XLP 患者淋巴细胞存在缺陷，但 SAP 在控制 EBV 感染方面的独特作用仍未得到解决。我们使用女性 XLP 携带者来解决这个问题，这些携带者由于随机 X 染色体失活，体内既有 SAP(+)细胞，也有 SAP(-)细胞。这代表了人类与小鼠混合骨髓嵌合体的等效物。虽然针对 CMV 和流感的记忆性 CD8(+) T 细胞分布在 SAP(+)和 SAP(-)群体中，但 EBV 特异性细胞仅为 SAP(+)。EBV 优先招募 SAP(+)细胞反映了 EBV 对 B 细胞的嗜性，以及 SAP 在 CD8(+) T 细胞中表达对于它们对 B 细胞呈递抗原的反应的必要性，但对其他细胞类型没有这种要求。SAP(-)克隆对 B 细胞呈递抗原的反应能力可以通过阻断 SLAM 受体 NTB-A 和 2B4 来克服，而在成纤维细胞上异位表达 NTB-A 抑制了 SAP(-)CD8(+) T 细胞的细胞毒性，从而证明了在没有 SAP 的情况下，SLAM 受体获得了抑制功能。创新性的 XLP 携带者模型使我们能够揭示 XLP 患者对 EBV 感染易感性的独特机制，而无需相关的动物模型。我们发现这反映了抗原呈递细胞的性质，而不是 EBV 本身。我们的数据还确定了一种病理性信号通路，可用于治疗严重 EBV 感染的患者。该系统可能允许研究其他人类疾病，这些疾病可利用随机 X 染色体失活的杂合基因表达。
