Collins Christopher M, Speck Samuel H
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
PLoS Pathog. 2014 May 1;10(5):e1004106. doi: 10.1371/journal.ppat.1004106. eCollection 2014 May.
X linked lymphoproliferative disease (XLP) is an inherited immunodeficiency resulting from mutations in the gene encoding the slam associated protein (SAP). One of the defining characteristics of XLP is extreme susceptibility to infection with Epstein-Barr virus (EBV), a gammaherpesvirus belonging to the genus Lymphocryptovirus, often resulting in fatal infectious mononucleosis (FIM). However, infection of SAP deficient mice with the related Murine gammaherpesvirus 68 (MHV68), a gammaherpesvirus in the genus Rhadinovirus, does not recapitulate XLP. Here we show that MHV68 inefficiently establishes latency in B cells in SAP deficient mice due to insufficient CD4 T cell help during the germinal center response. Although MHV68 infected B cells can be found in SAP-deficient mice, significantly fewer of these cells had a germinal center phenotype compared to SAP-sufficient mice. Furthermore, we show that infected germinal center B cells in SAP-deficient mice fail to proliferate. This failure to proliferate resulted in significantly lower viral loads, and likely accounts for the inability of MHV68 to induce a FIM-like syndrome. Finally, inhibiting differentiation of T follicular helper (TFH) cells in SAP-sufficient C57Bl/6 mice resulted in decreased B cell latency, and the magnitude of the TFH response directly correlated with the level of infection in B cells. This requirement for CD4 T cell help during the germinal center reaction by MHV68 is in contrast with EBV, which is thought to be capable of bypassing this requirement by expressing viral proteins that mimic signals provided by TFH cells. In conclusion, the outcome of MHV68 infection in mice in the setting of loss of SAP function is distinct from that observed in SAP-deficient patients infected with EBV, and may identify a fundamental difference between the strategies employed by the rhadinoviruses and lymphocryptoviruses to expand B cell latency during the early phase of infection.
X连锁淋巴细胞增生性疾病(XLP)是一种遗传性免疫缺陷病,由编码信号淋巴细胞激活分子相关蛋白(SAP)的基因突变引起。XLP的一个典型特征是极易感染爱泼斯坦-巴尔病毒(EBV),这是一种属于淋巴细胞病毒属的γ疱疹病毒,常导致致命性传染性单核细胞增多症(FIM)。然而,用相关的鼠γ疱疹病毒68(MHV68)感染缺乏SAP的小鼠,该病毒属于嗜淋巴细胞病毒属的一种γ疱疹病毒,并不会重现XLP的症状。我们在此表明,由于生发中心反应期间CD4 T细胞辅助不足,MHV68在缺乏SAP的小鼠B细胞中建立潜伏感染的效率低下。尽管在缺乏SAP的小鼠中可以发现被MHV68感染的B细胞,但与SAP充足的小鼠相比,具有生发中心表型的这类细胞明显较少。此外,我们表明,缺乏SAP的小鼠中被感染的生发中心B细胞无法增殖。这种增殖失败导致病毒载量显著降低,这可能是MHV68无法诱发类似FIM综合征的原因。最后,在SAP充足的C57Bl/6小鼠中抑制滤泡辅助性T(TFH)细胞的分化会导致B细胞潜伏感染减少,并且TFH反应的强度与B细胞中的感染水平直接相关。MHV68在生发中心反应期间对CD4 T细胞辅助的这种需求与EBV形成对比,EBV被认为能够通过表达模拟TFH细胞提供信号的病毒蛋白来绕过这一需求。总之,在SAP功能丧失的情况下,小鼠感染MHV68的结果与感染EBV的SAP缺陷患者所观察到的结果不同,这可能揭示了嗜淋巴细胞病毒属病毒和淋巴细胞病毒属病毒在感染早期扩展B细胞潜伏感染所采用策略之间的根本差异。