Murine gammaherpesvirus infection is skewed toward Igλ plus B cells expressing a specific heavy chain V-segment
Murine gammaherpesvirus infection is skewed toward Igλ plus B cells expressing a specific heavy chain V-segment
复制标题
DOI：
10.1371/journal.ppat.1008438
复制
发表时间：
2020-04-01
期刊：
影响因子：
6.7
通讯作者：
Speck, Samuel H.
中科院分区：
文献类型：
--
作者：
Collins, Christopher M.;Scharer, Christopher D.;Speck, Samuel H.
B细胞受体（BCR）的定义特征之一是构成BCR的免疫球蛋白基因库的广泛多样性，导致广泛的特异性。γ疱疹病毒是在B细胞中建立终身感染的亲B淋巴细胞病毒，并且尽管B细胞受体在B细胞生物学中起核心作用，但对γ疱疹病毒感染细胞的免疫球蛋白库知之甚少。为了开始表征由鼠γ疱疹病毒68（MHV 68）感染的细胞表达的IG基因，我们利用单细胞分选对感染的生殖中心（GC）B细胞和浆细胞的IG可变区进行测序和克隆。我们发现MHV 68感染偏向于表达IG λ轻链沿着单个重链可变基因IGHV 10 -1*01的细胞。该群体通过克隆扩增产生，但不是病毒抗原特异性的。此外，我们表明，类转换在MHV 68感染的细胞不同于未感染的细胞。与未感染的GC B细胞相比，更少的感染的GC B细胞发生类别转换，而与未感染的浆细胞相比，更多的感染的浆细胞发生类别转换。此外，尽管它们是生发中心衍生的，但大多数类别转换的浆细胞不显示体细胞超突变，无论感染状态如何。两者合计，这些数据表明，选择感染的B细胞与特定的BCR，以及病毒介导的操纵类转换和体细胞超变，是建立终身gammaherpesvirusininfection.Author summaryMurine gammaherpesvirus 68是一种啮齿动物病原体，是密切相关的人类gammaherpesviruses EB病毒和卡波西肉瘤相关病毒。所有已知的γ疱疹病毒都与淋巴瘤以及其他癌症的发展有关，在一小部分感染个体中，特别是那些免疫系统有潜在缺陷的个体（即，移植受者和HIV感染者）。由于人类γ疱疹病毒的小动物模型非常有限，因此对小鼠γ疱疹病毒68的研究可以为γ疱疹病毒感染的关键方面以及这些病毒与疾病发展的关联提供重要见解。所有γ疱疹病毒的另一个特征是它们能够建立对宿主的慢性感染，其中病毒在受感染个体的一生中维持。携带慢性丙种疱疹病毒感染的主要靶细胞是B淋巴细胞-免疫系统中产生抗体以应答感染的细胞。在这里，我们提供了一个详细的表征人口的B淋巴细胞，成为感染鼠γ疱疹病毒68。这导致鉴定出优先被病毒感染的特定B淋巴细胞群体。这支持了小鼠γ疱疹病毒感染B淋巴细胞不是随机的模型。然而，目前还不清楚为什么病毒针对这一特定的B细胞群体进行感染。
One of the defining characteristics of the B cell receptor (BCR) is the extensive diversity in the repertoire of immunoglobulin genes that make up the BCR, resulting in broad range of specificity. Gammaherpesviruses are B lymphotropic viruses that establish life-long infection in B cells, and although the B cell receptor plays a central role in B cell biology, very little is known about the immunoglobulin repertoire of gammaherpesvirus infected cells. To begin to characterize the Ig genes expressed by murine gammaherpesvirus 68 (MHV68) infected cells, we utilized single cell sorting to sequence and clone the Ig variable regions of infected germinal center (GC) B cells and plasma cells. We show that MHV68 infection is biased towards cells that express the Ig lambda light chain along with a single heavy chain variable gene, IGHV10-1*01. This population arises through clonal expansion but is not viral antigen specific. Furthermore, we show that class-switching in MHV68 infected cells differs from that of uninfected cells. Fewer infected GC B cells are class-switched compared to uninfected GC B cells, while more infected plasma cells are class-switched compared to uninfected plasma cells. Additionally, although they are germinal center derived, the majority of class switched plasma cells display no somatic hypermutation regardless of infection status. Taken together, these data indicate that selection of infected B cells with a specific BCR, as well as virus mediated manipulation of class switching and somatic hypermutation, are critical aspects in establishing life-long gammaherpesvirus infection.Author summaryMurine gammaherpesvirus 68 is a rodent pathogen that is closely related to the human gammaherpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated virus. All know gammaherpesviruses are associated with the development of lymphomas, as well as other cancers, in a small subset of infected individuals-particularly those with underlying defects in their immune system (i.e., transplant recipients and HIV infected patients). Because there are very limited small animal models for the human gammaherpesviruses, studies on murine gammaherepsviruses 68 can provide important insights into critical aspects of gammaherpesvirus infections and the association of these viruses with disease development. Another feature of all gammaherpesviruses is their ability to establish a chronic infection of their host-where the virus is maintained for the lifetime of the infected individual. The major target cell harboring chronic gammaherepsvirus infection are B lymphocytes-the cells in the immune system that produce antibodies in response to infections. Here we provide a detailed characterization of the populations of B lymphocytes that become infected by murine gammaherpesvirus 68. This has led to the identification of a specific population of B lymphocytes that is preferentially infected by the virus. This supports a model in which murine gammaherpesvirus infection of B lymphocytes is not random. However, it remains unclear why the virus targets this specific population of B cells for infection.