| 導(dǎo)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(yīng)的“罪魁禍?zhǔn)住笔洽裥透蓴_素。他們發(fā)現(xiàn)，病毒感染初期，細(xì)胞因子Ⅰ型干擾素會(huì)過(guò)早啟動(dòng)清除B淋巴細(xì)胞的通路，最終阻斷B細(xì)胞生成對(duì)抗病毒的中和性抗體。 |
淋巴細(xì)胞是免疫系統(tǒng)的基本成分，主要包括T淋巴細(xì)胞（T細(xì)胞）和B淋巴細(xì)胞（B細(xì)胞）。其中，B細(xì)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(xì)胞則不合成抗體，通過(guò)直接作用行使細(xì)胞免疫及免疫調(diào)節(jié)。
絕大多數(shù)病毒感染后，都會(huì)啟動(dòng)B細(xì)胞生成中和性抗體。但是對(duì)于少數(shù)引起慢性感染的病毒，例如HIV、乙肝病毒（HBV）以及小鼠淋巴細(xì)胞性脈絡(luò)叢腦膜炎病毒（LCMV），B細(xì)胞卻因?yàn)槟承┰驘o(wú)法啟動(dòng)抗體保護(hù)機(jī)制。
為了揭開(kāi)這些原因的真面目，來(lái)自于美國(guó)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(tuán)隊(duì)分別獨(dú)立試驗(yàn)，發(fā)現(xiàn)小鼠淋巴細(xì)胞性脈絡(luò)叢腦膜炎病毒（LCMV）之所以能夠抑制B細(xì)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(xì)胞因子，但是卻在面對(duì)LCMV病毒時(shí)表現(xiàn)出“壞”的一面。
他們發(fā)現(xiàn)：病毒感染初期，Ⅰ型干擾素表達(dá)量上調(diào)，會(huì)過(guò)早啟動(dòng)清除B淋巴細(xì)胞的通路，從而阻斷B細(xì)胞生成中和性抗體。當(dāng)封鎖Ⅰ型干擾素信號(hào)后，B細(xì)胞數(shù)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(xì)胞，但是它們會(huì)調(diào)控其他不同的免疫細(xì)胞參與清除B細(xì)胞。
幾十年來(lái)，免疫學(xué)家以淋巴細(xì)胞性脈絡(luò)叢腦膜炎病毒為模型，用于研究T細(xì)胞主導(dǎo)的免疫反應(yīng)，因?yàn)樵摬《緯?huì)減弱或者延遲B細(xì)胞產(chǎn)生抗體的能力。考慮到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(xù)感染抑制體液免疫的原因。
其中一支團(tuán)隊(duì)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?zhǔn)住?。?/p>
《Type I interferon suppresses virus-specific B cell responses by modulating CD8+ T cell differentiation》
美國(guó)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(tuán)隊(duì)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(xì)胞后發(fā)現(xiàn)，LCMV病毒感染的一周內(nèi)，B細(xì)胞都消失了。
正常情況下，病毒感染初期，機(jī)體免疫系統(tǒng)會(huì)高表達(dá)Ⅰ型干擾素，從而進(jìn)一步促進(jìn)B細(xì)胞的分化，最終增加中和性抗體的表達(dá)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(duì)于LCMV病毒而言，Ⅰ型干擾素似乎表現(xiàn)出“壞”的一面。當(dāng)研究團(tuán)隊(duì)在感染之前“封鎖”Ⅰ型干擾素受體后，小鼠脾臟內(nèi)B細(xì)胞的數(shù)量會(huì)急劇上升，促使B細(xì)胞表達(dá)更多的病毒中和抗體。
McGavern團(tuán)隊(duì)發(fā)現(xiàn)，在LCMV病毒感染最初，CD8+ T細(xì)胞會(huì)攻擊B細(xì)胞。因?yàn)橥ǔD8+ T細(xì)胞響應(yīng)病毒感染至少需要一周時(shí)間，感染最初T細(xì)胞的反應(yīng)讓研究團(tuán)隊(duì)很意外。但是他們通過(guò)反復(fù)試驗(yàn)，找到了T細(xì)胞識(shí)別并消滅B細(xì)胞的直接證據(jù)。
依據(jù)McGavern的研究，LCMV病毒通過(guò)與B細(xì)胞表面的受體結(jié)合而入侵B細(xì)胞，這些攜帶病毒的B細(xì)胞最終被CD8+ T細(xì)胞消滅，從而剝奪了它們生成中和性抗體的機(jī)會(huì)。
但是，辛辛那提大學(xué)醫(yī)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(xì)胞。所以，目前并不清楚為什么CD8+ T細(xì)胞會(huì)優(yōu)先攻擊帶有LCMV特異性受體的B細(xì)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(tuán)隊(duì)同樣發(fā)現(xiàn)了LCMV病毒感染初期B細(xì)胞被清除的現(xiàn)象。他們證實(shí)，B細(xì)胞的失活由Ⅰ型干擾素信號(hào)介導(dǎo)。而且他們發(fā)現(xiàn)，骨髓細(xì)胞、樹(shù)突狀細(xì)胞和T細(xì)胞都參與其中。
Pinschewer表示，Ⅰ型干擾素信號(hào)涉及眾多下游因子，這可能是多種因素參與的共同結(jié)果。他認(rèn)為，Ⅰ型干擾素抑制B細(xì)胞響應(yīng)抗體免疫的機(jī)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(qiáng)調(diào)，Ⅰ型干擾素對(duì)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(fù)面效應(yīng)的方法，做到“揚(yáng)長(zhǎng)避短”。
《Inflammatory monocytes hinder antiviral B cell responses》
Iannacone團(tuán)隊(duì)給小鼠注射的B細(xì)胞都攜帶有熒光標(biāo)記，且這些B細(xì)胞都能夠與LCMV病毒或者水泡性口炎病毒（VSV）特異性識(shí)別。VSV病毒同樣會(huì)引發(fā)強(qiáng)烈的抗體反應(yīng)。
注射B細(xì)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(yīng)的小鼠，并記錄小鼠體內(nèi)B細(xì)胞在淋巴結(jié)附近的運(yùn)動(dòng)軌跡。
結(jié)果顯示，病毒感染后，兩種B細(xì)胞都離開(kāi)淋巴結(jié)濾泡，與淋巴結(jié)其他區(qū)域的被感染細(xì)胞互作。但是，僅僅只有靶向VSV病毒的B細(xì)胞會(huì)重新返回濾泡，在這一場(chǎng)所它們會(huì)繼續(xù)成熟，并生成中和抗體。而靶向LCMV病毒的B細(xì)胞會(huì)在濾泡外逗留至少3天，并與附近的單核細(xì)胞互作。
最糟糕的是，單核細(xì)胞會(huì)分泌一氧化氮合成酶，吞噬掉B細(xì)胞。在這一過(guò)程中，Ⅰ型干擾素起著關(guān)鍵作用。在缺乏Ⅰ型干擾素受體的小鼠模型中，單核細(xì)胞并不會(huì)遷移至淋巴結(jié)位置，從而確保B細(xì)胞“免于一死”。
與McGavern團(tuán)隊(duì)不同的是，Iannacone團(tuán)隊(duì)并未發(fā)現(xiàn)CD8+ T細(xì)胞攻擊B細(xì)胞的證據(jù)。相應(yīng)得，McGavern團(tuán)隊(duì)也未報(bào)道任何單核細(xì)胞吞噬B細(xì)胞的結(jié)論。
Iannacone解釋說(shuō)：“Ⅰ型干擾素對(duì)免疫細(xì)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.
展開(kāi)還沒(méi)有人評(píng)論，趕快搶個(gè)沙發(fā)
