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

剖析 HVEM 和 BTLA 在限制生发中心 B 细胞反应中的作用

• 批准号: 9327554
• 负责人: Michelle Mintz
• 金额: $ 3.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327554
• 关键词: Achievement; Affinity; Alpha Cell; Antibody Affinity; Antigens; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Binding; Biology; CD4 Positive T Lymphocytes; Cell Communication; Cellular biology; Cues; Diffuse; Follicular Lymphoma; Gene Targeting; Generations; Growth; Helper-Inducer T-Lymphocyte; Humoral Immunities; ITIM; Immune response; Immunize; Immunoglobulin Genes; Immunoglobulin Somatic Hypermutation; Immunoglobulins; Immunotherapy; Interleukin-4; Kinetics; Lead; Ligands; Lymphoid; Malignant - descriptor; Memory B-Lymphocyte; Microscopy; Molecular; Mutate; Mutation; Organ; PTPN6 gene; Phosphoric Monoester Hydrolases; Plasma Cells; Process; Production; Public Health; Reaction; Recruitment Activity; Role; Signal Transduction; Structure of germinal center of lymph node; T-Lymphocyte; TNFRSF1A gene; TNFSF5 gene; Testing; Vaccines; Work; antigen binding; cell growth; experimental study; herpesvirus entry mediator; high voltage electron microscopy; immunological synapse; improved; large cell Diffuse non-Hodgkin' s lymphoma; member; novel; novel vaccines; pathogen; protein function; receptor; response; two-photon; vaccine development

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.

项目总结/文摘