| 导读 | 10月21日，Science子刊《Science Immunology》连发3篇文章揭示，慢性感染病毒抑制免疫响应的“罪魁祸首”是Ⅰ型干扰素。他们发现，病毒感染初期，细胞因子Ⅰ型干扰素会过早启动清除B淋巴细胞的通路，最终阻断B细胞生成对抗病毒的中和性抗体。 |
淋巴细胞是免疫系统的基本成分，主要包括T淋巴细胞（T细胞）和B淋巴细胞（B细胞）。其中，B细胞通过生产多种抗体，发挥体液免疫，抵御外来病原物。而T细胞则不合成抗体，通过直接作用行使细胞免疫及免疫调节。
绝大多数病毒感染后，都会启动B细胞生成中和性抗体。但是对于少数引起慢性感染的病毒，例如HIV、乙肝病毒（HBV）以及小鼠淋巴细胞性脉络丛脑膜炎病毒（LCMV），B细胞却因为某些原因无法启动抗体保护机制。
为了揭开这些原因的真面目，来自于美国神经类疾病和中风研究所、意大利圣拉斐尔科学研究所、瑞士巴塞尔大学的3支研究团队分别独立试验，发现小鼠淋巴细胞性脉络丛脑膜炎病毒（LCMV）之所以能够抑制B细胞生成抗体，得益于Ⅰ型干扰素（IFN-I）的“坏影响”。3篇文章于同一天发表在《Science Immunology》期刊。
Ⅰ型干扰素的“叛变”
Ⅰ型干扰素原本是参与抗病毒免疫的重要细胞因子，但是却在面对LCMV病毒时表现出“坏”的一面。
他们发现：病毒感染初期，Ⅰ型干扰素表达量上调，会过早启动清除B淋巴细胞的通路，从而阻断B细胞生成中和性抗体。当封锁Ⅰ型干扰素信号后，B细胞数量会增加。虽然这3篇研究表明，Ⅰ型干扰素并不会直接作用于B细胞，但是它们会调控其他不同的免疫细胞参与清除B细胞。
几十年来，免疫学家以淋巴细胞性脉络丛脑膜炎病毒为模型，用于研究T细胞主导的免疫反应，因为该病毒会减弱或者延迟B细胞产生抗体的能力。考虑到HIV、HBV等病毒同样也会抑制抗体生成，科学家们选择以LCMV病毒作为模型，试图解析病毒持续感染抑制体液免疫的原因。
其中一支团队的带头人、圣拉斐尔科学研究所的免疫学家Matteo Iannacone表示：“3篇研究都证实，Ⅰ型干扰素是‘罪魁祸首’。”
《Type I interferon suppresses virus-specific B cell responses by modulating CD8+ T cell differentiation》
美国神经类疾病和中风研究所的病毒免疫学家Dorian McGavern带领团队以健康小鼠为研究模型，通过注射特异性靶向LCMV病毒的B细胞后发现，LCMV病毒感染的一周内，B细胞都消失了。
正常情况下，病毒感染初期，机体免疫系统会高表达Ⅰ型干扰素，从而进一步促进B细胞的分化，最终增加中和性抗体的表达量。McGavern 表示：“Ⅰ型干扰素是敲响免疫警钟的最重要因子。”
但是，对于LCMV病毒而言，Ⅰ型干扰素似乎表现出“坏”的一面。当研究团队在感染之前“封锁”Ⅰ型干扰素受体后，小鼠脾脏内B细胞的数量会急剧上升，促使B细胞表达更多的病毒中和抗体。
McGavern团队发现，在LCMV病毒感染最初，CD8+ T细胞会攻击B细胞。因为通常CD8+ T细胞响应病毒感染至少需要一周时间，感染最初T细胞的反应让研究团队很意外。但是他们通过反复试验，找到了T细胞识别并消灭B细胞的直接证据。
依据McGavern的研究，LCMV病毒通过与B细胞表面的受体结合而入侵B细胞，这些携带病毒的B细胞最终被CD8+ T细胞消灭，从而剥夺了它们生成中和性抗体的机会。
但是，辛辛那提大学医学院的免疫学家Steven Waggoner表示，LCMV病毒并不会特异性入侵B细胞。所以，目前并不清楚为什么CD8+ T细胞会优先攻击带有LCMV特异性受体的B细胞。
《Interferon-driven deletion of antiviral B cells at the onset of chronic infection》
在这一篇学术文章中，巴塞尔大学的病毒学家Daniel Pinschewer团队同样发现了LCMV病毒感染初期B细胞被清除的现象。他们证实，B细胞的失活由Ⅰ型干扰素信号介导。而且他们发现，骨髓细胞、树突状细胞和T细胞都参与其中。
Pinschewer表示，Ⅰ型干扰素信号涉及众多下游因子，这可能是多种因素参与的共同结果。他认为，Ⅰ型干扰素抑制B细胞响应抗体免疫的机理可以给其他包括HIV、HBV等病毒感染提供研究的新线索。
Pinschewer强调，Ⅰ型干扰素对于防御病毒至关重要，所以科学家们有必要快速找到消除它们负面效应的方法，做到“扬长避短”。
《Inflammatory monocytes hinder antiviral B cell responses》
Iannacone团队给小鼠注射的B细胞都携带有荧光标记，且这些B细胞都能够与LCMV病毒或者水泡性口炎病毒（VSV）特异性识别。VSV病毒同样会引发强烈的抗体反应。
注射B细胞之后，研究人员将LCMV病毒或者VSV病毒通过皮肤感染响应的小鼠，并记录小鼠体内B细胞在淋巴结附近的运动轨迹。
结果显示，病毒感染后，两种B细胞都离开淋巴结滤泡，与淋巴结其他区域的被感染细胞互作。但是，仅仅只有靶向VSV病毒的B细胞会重新返回滤泡，在这一场所它们会继续成熟，并生成中和抗体。而靶向LCMV病毒的B细胞会在滤泡外逗留至少3天，并与附近的单核细胞互作。
最糟糕的是，单核细胞会分泌一氧化氮合成酶，吞噬掉B细胞。在这一过程中，Ⅰ型干扰素起着关键作用。在缺乏Ⅰ型干扰素受体的小鼠模型中，单核细胞并不会迁移至淋巴结位置，从而确保B细胞“免于一死”。
与McGavern团队不同的是，Iannacone团队并未发现CD8+ T细胞攻击B细胞的证据。相应得，McGavern团队也未报道任何单核细胞吞噬B细胞的结论。
Iannacone解释说：“Ⅰ型干扰素对免疫细胞不同的影响可能取决于病毒感染的位置和时间。”
参考资料：
Culprit for Antibody Blockade Identified
Studies have established a role for T cells in resolving persistent viral infections, yet emerging evidence indicates that both T and B cells are required to control some viruses. During persistent infection, a marked lag or failure to generate neutralizing antibodies is commonly observed and likely contributes to an inability to control certain pathogens. Using lymphocytic choriomeningitis virus (LCMV) as a model, we have examined how a persistent viral infection can suppress neutralizing humoral immunity. By tracking the fate of virus-specific B cells in vivo, we report that LCMV-specific B cells were rapidly deleted within a few days of persistent infection, and this deletion was completely reversed by blockade of type I interferon (IFN-I) signaling. Early interference with IFN-I signaling promoted survival and differentiation of LCMV-specific B cells, which accelerated the generation of neutralizing antibodies. This marked improvement in antiviral humoral immunity did not rely on the cessation of IFN-I signaling in B cells but on alterations in the virus-specific CD8+ T cell response. Using two-photon microscopy and in vivo calcium imaging, we observed that cytotoxic T lymphocytes (CTLs) productively engaged and killed LCMV-specific B cells in a perforin-dependent manner within the first few days of infection. Blockade of IFN-I signaling protected LCMV-specific B cells by promoting CTL dysfunction. Therapeutic manipulation of this pathway may facilitate efforts to promote humoral immunity during persistent viral infection in humans. Our findings illustrate how events that occur early after infection can disturb the resultant adaptive response and contribute to viral persistence.
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Antibodies are critical for protection against viral infections. However, several viruses, such as lymphocytic choriomeningitis virus (LCMV), avoid the induction of early protective antibody responses by poorly understood mechanisms. We analyzed the spatiotemporal dynamics of B cell activation to show that, upon subcutaneous infection, LCMV-specific B cells readily relocate to the interfollicular and T cell areas of draining lymph nodes, where they extensively interact with CD11b+Ly6Chi inflammatory monocytes. These myeloid cells were recruited to lymph nodes draining LCMV infection sites in a type I interferon– and CCR2-dependent fashion, and they suppressed antiviral B cell responses by virtue of their ability to produce nitric oxide. Depletion of inflammatory monocytes, inhibition of their lymph node recruitment, or impairment of their nitric oxide–producing ability enhanced LCMV-specific B cell survival and led to robust neutralizing antibody production. Our results identify inflammatory monocytes as critical gatekeepers that restrain antiviral B cell responses and suggest that certain viruses take advantage of these cells to prolong their persistence within the host.
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Inadequate antibody responses and perturbed B cell compartments represent hallmarks of persistent microbial infections, but the mechanisms whereby persisting pathogens suppress humoral immunity remain poorly defined. Using adoptive transfer experiments in the context of a chronic lymphocytic choriomeningitis virus infection of mice, we have documented rapid depletion of virus-specific B cells that coincided with the early type I interferon (IFN-I) response to infection. We found that the loss of activated B cells was driven by IFN-I signaling to several cell types including dendritic cells, T cells, and myeloid cells. This process was independent of B cell–intrinsic IFN-I sensing and resulted from biased differentiation of na?ve B cells into short-lived antibody-secreting cells. The ability to generate robust B cell responses was restored upon IFN-I receptor blockade or, partially, when experimentally depleting myeloid cells or the IFN-I–induced cytokines interleukin-10 and tumor necrosis factor–α. We have termed this IFN-I–driven depletion of B cells “B cell decimation.” Strategies to counter B cell decimation should thus help us better leverage humoral immunity in the combat against persistent microbial diseases.
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