Expansion of murine gammaherpesvirus latently infected B cells requires T follicular help.
Expansion of murine gammaherpesvirus latently infected B cells requires T follicular help.
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DOI：
10.1371/journal.ppat.1004106
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发表时间：
2014-05
期刊：
影响因子：
6.7
通讯作者：
Speck SH
中科院分区：
文献类型：
--
作者：
Collins CM;Speck SH
X 连锁淋巴组织增生性疾病 (XLP) 是一种遗传性免疫缺陷，由编码 slam 相关蛋白 (SAP) 的基因突变引起。 XLP 的一个决定性特征是极易感染 Epstein-Barr 病毒 (EBV)，这是一种属于淋巴隐病毒属的伽玛疱疹病毒，通常会导致致命的传染性单核细胞增多症 (FIM)。然而，SAP 缺陷小鼠感染相关的鼠伽马疱疹病毒 68 (MHV68)（一种属于红病毒属的伽马疱疹病毒）后，不会重现 XLP。在这里，我们发现，由于在生发中心反应期间 CD4 T 细胞帮助不足，MHV68 在 SAP 缺陷小鼠的 B 细胞中无效地建立潜伏期。尽管在 SAP 缺陷小鼠中可以发现 MHV68 感染的 B 细胞，但与 SAP 充足的小鼠相比，这些细胞具有生发中心表型的数量明显较少。此外，我们发现 SAP 缺陷小鼠中受感染的生发中心 B 细胞无法增殖。这种增殖失败导致病毒载量显着降低，并且可能解释了 MHV68 无法诱导 FIM 样综合征的原因。最后，抑制 SAP 充足的 C57Bl/6 小鼠中滤泡辅助 T (TFH) 细胞的分化导致 B 细胞潜伏期缩短，并且 TFH 反应的强度与 B 细胞的感染水平直接相关。 MHV68 在生发中心反应过程中对 CD4 T 细胞帮助的这种要求与 EBV 形成鲜明对比，EBV 被认为能够通过表达模仿 TFH 细胞提供的信号的病毒蛋白来绕过这一要求。总之，在 SAP 功能丧失的情况下，小鼠中 MHV68 感染的结果与在感染 EBV 的 SAP 缺陷患者中观察到的结果不同，并且可能确定了病毒和淋巴隐病毒在感染早期阶段延长 B 细胞潜伏期所采用的策略之间的根本区别。在免疫反应过程中，B 细胞通过在生发中心反应期间经历大规模扩张来应对入侵的病原体。这种增殖需要来自 CD4 T 细胞的信号，其中一些 B 细胞随后成熟为分泌抗体的浆细胞，而另一些则成熟为可在宿主生命中持续存在的记忆 B 细胞。伽马疱疹病毒通过感染 B 细胞来利用这种免疫反应，导致生发中心反应期间受感染细胞库的扩大。人类伽马疱疹病毒 Epstein-Barr 病毒 (EBV) 被认为能够通过表达模拟 CD4 T 细胞信号的病毒蛋白来实现这一目标，而无需 CD4 T 细胞的帮助。在这里，我们在伽马疱疹病毒感染的小鼠模型中证明，受感染的 B 细胞需要来自 CD4 T 细胞的信号才能增殖。由于小鼠伽马疱疹病毒和 EBV 属于伽马疱疹病毒的不同亚组，这表明这些亚组在潜伏期建立期间利用根本不同的策略来扩大受感染 B 细胞库。这些不同的策略可以解释在 CD4 T 细胞帮助缺陷导致生发中心反应缺陷的情况下，这些不同亚型的伽玛疱疹病毒感染的不同结果。
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. During an immune response, B cells respond to invading pathogens by undergoing massive expansion during the germinal center reaction. This proliferation requires signals from CD4 T cells, with some B cells then maturing into antibody secreting plasma cells, while others mature into memory B cells that may persist for the life of the host. Gammaherpesviruses take advantage of this immune response by infecting B cells, resulting in expansion of the pool of infected cells during the germinal center reaction. The human gammaherpesvirus Epstein-Barr virus (EBV) is thought to be able to accomplish this without the need for CD4 T cell help by expressing viral proteins that mimic signals from CD4 T cells. Here we show in a mouse model of gammaherpesvirus infection that infected B cells require signals from CD4 T cells for proliferation. Since the mouse gammaherpesvirus and EBV belong to different subgroups of gammaherpesviruses, this suggests that these subgroups utilize fundamentally different strategies to expand the pool of infected B cells during the establishment of latency. These different strategies may explain the different outcome of infection by these different subgroups of gammaherpesviruses in the context of defective germinal center responses that result from defective CD4 T cell help.
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