| 導讀 | 10月21日，Science子刊《Science Immunology》連發(fā)3篇文章揭示，慢性感染病毒抑制免疫響應的“罪魁禍首”是Ⅰ型干擾素。他們發(fā)現，病毒感染初期，細胞因子Ⅰ型干擾素會(huì )過(guò)早啟動(dòng)清除B淋巴細胞的通路，最終阻斷B細胞生成對抗病毒的中和性抗體。 |
淋巴細胞是免疫系統的基本成分，主要包括T淋巴細胞（T細胞）和B淋巴細胞（B細胞）。其中，B細胞通過(guò)生產(chǎn)多種抗體，發(fā)揮體液免疫，抵御外來(lái)病原物。而T細胞則不合成抗體，通過(guò)直接作用行使細胞免疫及免疫調節。
絕大多數病毒感染后，都會(huì )啟動(dòng)B細胞生成中和性抗體。但是對于少數引起慢性感染的病毒，例如HIV、乙肝病毒（HBV）以及小鼠淋巴細胞性脈絡(luò )叢腦膜炎病毒（LCMV），B細胞卻因為某些原因無(wú)法啟動(dòng)抗體保護機制。
為了揭開(kāi)這些原因的真面目，來(lái)自于美國神經(jīng)類(lèi)疾病和中風(fēng)研究所、意大利圣拉斐爾科學(xué)研究所、瑞士巴塞爾大學(xué)的3支研究團隊分別獨立試驗，發(fā)現小鼠淋巴細胞性脈絡(luò )叢腦膜炎病毒（LCMV）之所以能夠抑制B細胞生成抗體，得益于Ⅰ型干擾素（IFN-I）的“壞影響”。3篇文章于同一天發(fā)表在《Science Immunology》期刊。
Ⅰ型干擾素的“叛變”
Ⅰ型干擾素原本是參與抗病毒免疫的重要細胞因子，但是卻在面對LCMV病毒時(shí)表現出“壞”的一面。
他們發(fā)現：病毒感染初期，Ⅰ型干擾素表達量上調，會(huì )過(guò)早啟動(dòng)清除B淋巴細胞的通路，從而阻斷B細胞生成中和性抗體。當封鎖Ⅰ型干擾素信號后，B細胞數量會(huì )增加。雖然這3篇研究表明，Ⅰ型干擾素并不會(huì )直接作用于B細胞，但是它們會(huì )調控其他不同的免疫細胞參與清除B細胞。
幾十年來(lái)，免疫學(xué)家以淋巴細胞性脈絡(luò )叢腦膜炎病毒為模型，用于研究T細胞主導的免疫反應，因為該病毒會(huì )減弱或者延遲B細胞產(chǎn)生抗體的能力?？紤]到HIV、HBV等病毒同樣也會(huì )抑制抗體生成，科學(xué)家們選擇以L(fǎng)CMV病毒作為模型，試圖解析病毒持續感染抑制體液免疫的原因。
其中一支團隊的帶頭人、圣拉斐爾科學(xué)研究所的免疫學(xué)家Matteo Iannacone表示：“3篇研究都證實(shí)，Ⅰ型干擾素是‘罪魁禍首’?！?/p>
《Type I interferon suppresses virus-specific B cell responses by modulating CD8+ T cell differentiation》
美國神經(jīng)類(lèi)疾病和中風(fēng)研究所的病毒免疫學(xué)家Dorian McGavern帶領(lǐng)團隊以健康小鼠為研究模型，通過(guò)注射特異性靶向LCMV病毒的B細胞后發(fā)現，LCMV病毒感染的一周內，B細胞都消失了。
正常情況下，病毒感染初期，機體免疫系統會(huì )高表達Ⅰ型干擾素，從而進(jìn)一步促進(jìn)B細胞的分化，最終增加中和性抗體的表達量。McGavern 表示：“Ⅰ型干擾素是敲響免疫警鐘的最重要因子?！?/p>
但是，對于LCMV病毒而言，Ⅰ型干擾素似乎表現出“壞”的一面。當研究團隊在感染之前“封鎖”Ⅰ型干擾素受體后，小鼠脾臟內B細胞的數量會(huì )急劇上升，促使B細胞表達更多的病毒中和抗體。
McGavern團隊發(fā)現，在LCMV病毒感染最初，CD8+ T細胞會(huì )攻擊B細胞。因為通常CD8+ T細胞響應病毒感染至少需要一周時(shí)間，感染最初T細胞的反應讓研究團隊很意外。但是他們通過(guò)反復試驗，找到了T細胞識別并消滅B細胞的直接證據。
依據McGavern的研究，LCMV病毒通過(guò)與B細胞表面的受體結合而入侵B細胞，這些攜帶病毒的B細胞最終被CD8+ T細胞消滅，從而剝奪了它們生成中和性抗體的機會(huì )。
但是，辛辛那提大學(xué)醫學(xué)院的免疫學(xué)家Steven Waggoner表示，LCMV病毒并不會(huì )特異性入侵B細胞。所以，目前并不清楚為什么CD8+ T細胞會(huì )優(yōu)先攻擊帶有LCMV特異性受體的B細胞。
《Interferon-driven deletion of antiviral B cells at the onset of chronic infection》
在這一篇學(xué)術(shù)文章中，巴塞爾大學(xué)的病毒學(xué)家Daniel Pinschewer團隊同樣發(fā)現了LCMV病毒感染初期B細胞被清除的現象。他們證實(shí)，B細胞的失活由Ⅰ型干擾素信號介導。而且他們發(fā)現，骨髓細胞、樹(shù)突狀細胞和T細胞都參與其中。
Pinschewer表示，Ⅰ型干擾素信號涉及眾多下游因子，這可能是多種因素參與的共同結果。他認為，Ⅰ型干擾素抑制B細胞響應抗體免疫的機理可以給其他包括HIV、HBV等病毒感染提供研究的新線(xiàn)索。
Pinschewer強調，Ⅰ型干擾素對于防御病毒至關(guān)重要，所以科學(xué)家們有必要快速找到消除它們負面效應的方法，做到“揚長(cháng)避短”。
《Inflammatory monocytes hinder antiviral B cell responses》
Iannacone團隊給小鼠注射的B細胞都攜帶有熒光標記，且這些B細胞都能夠與LCMV病毒或者水泡性口炎病毒（VSV）特異性識別。VSV病毒同樣會(huì )引發(fā)強烈的抗體反應。
注射B細胞之后，研究人員將LCMV病毒或者VSV病毒通過(guò)皮膚感染響應的小鼠，并記錄小鼠體內B細胞在淋巴結附近的運動(dòng)軌跡。
結果顯示，病毒感染后，兩種B細胞都離開(kāi)淋巴結濾泡，與淋巴結其他區域的被感染細胞互作。但是，僅僅只有靶向VSV病毒的B細胞會(huì )重新返回濾泡，在這一場(chǎng)所它們會(huì )繼續成熟，并生成中和抗體。而靶向LCMV病毒的B細胞會(huì )在濾泡外逗留至少3天，并與附近的單核細胞互作。
最糟糕的是，單核細胞會(huì )分泌一氧化氮合成酶，吞噬掉B細胞。在這一過(guò)程中，Ⅰ型干擾素起著(zhù)關(guān)鍵作用。在缺乏Ⅰ型干擾素受體的小鼠模型中，單核細胞并不會(huì )遷移至淋巴結位置，從而確保B細胞“免于一死”。
與McGavern團隊不同的是，Iannacone團隊并未發(fā)現CD8+ T細胞攻擊B細胞的證據。相應得，McGavern團隊也未報道任何單核細胞吞噬B細胞的結論。
Iannacone解釋說(shuō)：“Ⅰ型干擾素對免疫細胞不同的影響可能取決于病毒感染的位置和時(shí)間?！?
參考資料：
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.
展開(kāi)
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.
展開(kāi)
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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