Dissecting the role of HVEM and BTLA in constraining the germinal center B cell response

项目概要/摘要 生发中心（GC）是淋巴器官中的区域，其中活化的B细胞因其能力而被选择， 以高亲和力结合抗原并产生记忆B细胞和高亲和力抗体。GC B细胞具有 在免疫应答过程中，通过免疫抑制剂提高它们对免疫抗原的亲和力的独特能力， 体细胞超突变和选择的过程。虽然体细胞超变的目标是免疫球蛋白 基因，脱靶突变也会发生，并导致GC B细胞恶性转化为亚群 非何杰金B细胞淋巴瘤。我们对GC B细胞生物学的理解得到了极大的丰富， 了解这些突变如何超越正常限制GC B细胞生长。例如，我们的实验室 已经显示了S1 PR 2在将GC B细胞限制于GC中并通过拮抗Akt信号传导抑制生长中的作用。 HVEM是TNF受体超家族成员之一，也称为TNFRSF 14，在衰老中心经常发生突变， (GC)衍生的非霍奇金B细胞淋巴瘤，如滤泡性淋巴瘤和弥漫性大B细胞淋巴瘤。 在HVEM中发现的突变被预测会导致蛋白质功能的丧失，这表明了一个重要的基因突变。 HVEM在GC B细胞中的生长调节作用。然而，HVEM在B细胞中的功能尚未被直接研究。 考察HVEM在滤泡B细胞上高度表达，在GC B细胞上以较低水平表达， 这可能暗示了GC中更精细调节的信号传导的优点。在初步研究中我们发现 HVEM的缺陷导致GC B细胞的细胞内在扩增。HVEM的结合伙伴， 免疫球蛋白（IG）超家族共抑制受体B和T淋巴细胞衰减因子（BTLA）是最高 在GC中表示。BTLA在T滤泡辅助细胞（Tfh）上高度表达，BTLA缺乏抗原- 特异性CD 4 + T细胞增加IL-21的产生和GC B细胞的扩增，表明BTLA的调节作用 在Tfh细胞上。Tfh细胞在GC B细胞选择中具有关键作用，并且已经研究了几种分子调节剂。 显示调节提供给GC B细胞的T细胞帮助的程度。我们假设HVEM作为一种 通过与BTLA相互作用抑制GC B细胞应答，BTLA是B和T的潜在负调节剂 细胞接合。具体来说，我们的目标是评估HVEM如何调节GC B细胞反应的大小 以及它是否影响长期体液免疫的诱导（1）;并检查T细胞上BTLA的表达是否 滤泡辅助细胞调节GC反应期间T细胞辅助的量（2）。这项工作将定义一个 GC B细胞应答的新型负调节剂，其可导致疫苗开发的合理靶点， 免疫疗法和GC衍生的B细胞淋巴瘤的治疗。

Project summary/abstract Germinal centers (GC) are regions in lymphoid organs where activated B cells are selected for their ability to bind antigen with high affinity as well as generate memory B cells and high affinity antibodies. GC B cells have the unique ability to improve their affinity to the immunizing antigen during an immune response through a process of somatic hypermutation and selection. Although somatic hypermutation targets the immunoglobulin genes, off-target mutations also occur and contribute to the malignant transformation of GC B cells into a subset of non-Hodgkin B cell lymphomas. Our understanding of GC B cell biology has been greatly enriched by understanding how such mutations over-ride the normal constraints to GC B cell growth. For instance, our lab has shown S1PR2’s role in confining GC B cells to the GC and inhibiting growth by antagonizing Akt signaling. HVEM, a TNF receptor superfamily member (also called TNFRSF14), is frequently mutated in germinal center (GC) derived non-Hodgkin B cell lymphomas such as follicular lymphoma and diffuse large B cell lymphoma. The mutations found in HVEM are predicted to lead to loss of the protein’s function, suggesting an important growth regulatory role for HVEM in GC B cells. However, HVEM’s function in B cells has not been directly examined. HVEM is highly expressed on follicular B cells and is expressed at a lower level on GC B cells, possibly suggesting an advantage to more finely tuned signaling in the GC. In preliminary studies we have found that deficiency in HVEM results in a cell intrinsic expansion of GC B cells. Of HVEM’s binding partners, the immunoglobulin (Ig) superfamily co-inhibitory receptor B and T lymphocyte attenuator (BTLA) is most highly expressed in the GC. BTLA is highly expressed on T follicular helper (Tfh) cells and BTLA deficiency in antigen- specific CD4+ T cells increases IL-21 production and GC B cell expansion, suggesting a regulatory role of BTLA on Tfh cells. Tfh cells have a crucial role in GC B cell selection and several molecular regulators have been shown to tune the degree of T cell help provided to the GC B cell. We hypothesize that HVEM acts as a suppressor of GC B cell responses through its interaction with BTLA, a potential negative regulator of B and T cell engagement. Specifically, we aim to assess how HVEM regulates the magnitude of the GC B cell response and if it impacts the induction of long-lived humoral immunity (1); and to examine if BTLA expression on T follicular helper cells moderates the amount of T cell help during the GC reaction (2). This work will define a novel negative regulator of the GC B cell response, which can lead to a rational target for vaccine development, immunotherapy, and treatment for GC-derived B cell lymphomas.