The Role of Follicular CD8+ T Cells in Pathogenesis of AIDS-NHL

滤泡 CD8 T 细胞在 AIDS-NHL 发病机制中的作用

基本信息

批准号：
10305996
负责人：
Marta Epeldegui
金额：
$ 5.46万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10305996
关键词：
AIDS-Related Lymphoma AIDS-Related Non-Hodgkin&apos s Lymphoma Accounting Acquired Immunodeficiency Syndrome Antibodies Antibody Formation Antigens B-Cell Activation B-Cell Lymphomas B-Lymphocytes BCL6 gene BLR1 gene Binding Proteins Blood Blood Circulation CCR5 gene CD19 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CXCL10 gene CXCL13 gene CXCR3 gene CXCR4 gene Cell Communication Cell physiology Cells Cessation of life Chronic Coculture Techniques Complement Country Cryopreservation Cytomegalovirus Cytometry DNA Data Development Diagnosis Disease Environment Event Exhibits Functional disorder Generations Grant Growth HIV HIV Infections HIV Seropositivity HIV-1 Helper-Inducer T-Lymphocyte Hepatitis B Human Herpesvirus 4 Image Immune Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin Genes Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunoglobulins Impairment Individual Infection Inflammation Interleukin-10 Interleukin-6 Lead Light Lymphoma cell Lymphomagenesis Maintenance Measures Mediating Mitogens Molecular Mutation Names Non-Hodgkin&apos s Lymphoma Oncogenes Oncogenic Parents Participant Pathogenesis Patients Peripheral Peripheral Blood Mononuclear Cell Play Population Production Public Health Reporting Research Resources Rheumatoid Arthritis Risk Role Structure of germinal center of lymph node Systemic Lupus Erythematosus T cell response T memory cell T-Lymphocyte TNF gene TNFRSF5 gene TNFSF5 gene Testing The Multicenter AIDS Cohort Study Tissues Tumor Subtype Virus Diseases Virus Receptors Work activation-induced cytidine deaminase antiretroviral therapy combat cytokine cytotoxic cytotoxic CD8 T cells exhaust exhaustion high dimensionality immune activation microbial novel parent grant pathogen peripheral blood programmed cell death ligand 1 response transcription factor tumor tumor growth tumor microenvironment virtual

项目摘要

PROJECT SUMMARY HIV-infected individuals are at an increased risk of developing non-Hodgkin lymphoma (NHL). Virtually all AIDS- related lymphomas (ARL) are of B-cell origin. Two major mechanisms are thought to contribute to the genesis of ARL: 1) loss of immune-mediated control of EBV+ B-cells and their transformation as a result of impaired T- cell function late in the course of HIV disease, and 2) chronic B-cell activation leading to DNA-modifying events that contribute to oncogene mutations/translocations. Thus, both chronic B-cell activation and impaired T-cell function are important contributors to lymphomagenesis. We and others have shown that elevated levels of several cytokines (IL-6, IL-10, CXCL13, TNFα, and IP-10/CXCL10), molecules associated with B-cell activation (sCD23, sCD27, sCD30, κ and λ-immunoglobulin free-light-chains), and microbial translocation factors (e.g. lipopolyssacharide-binding protein (LPB), sCD14, EndoCab) precede the development of AIDS-related NHL (ARL). In addition, B-regulatory cells (Bregs) (CD19+CD24+CD38+), which also express programmed death- ligand 1 (PD-L1) and secrete IL-10, are significantly elevated in peripheral blood of HIV positive individuals who develop ARL. Therefore, inflammation and microbial translocation precede the development of ARL and play an important role in lymphomagenesis. Recently, a novel population of CD4+ helper T-cells has been described (CXCR5-CXCR3+PD-1hi CD4+), which have been named peripheral T-helper cells (TPH). TPH cells have been reported in blood and chronically inflamed peripheral tissues of rheumatoid arthritis and systemic lupus erythematosus patients. TPH cells have B-cell activating capacities and secrete IL-10. We hypothesize that TPH cells accumulate in peripheral tissues in response to inflammation and microbial translocation during HIV infection while inducing B-cell activation, and play a role in the development and maintenance of the tumor niche, thus, contributing to lymphomagenesis and tumor growth, as well as B-cell dysfunction. In this study, we will test this hypothesis by determining if: 1) TPH cells isolated from HIV-positive and negative individuals induce B-cell activation and/or differentiation, and/or induce the expression of Breg cell markers known to be associated with risk for ARL (Aim 1); if 2) immune activation-associated inflammation and/or microbial translocation contribute to the generation of TPH cells (Aim 2); and if 3) TPH cells form part of the tumor microenvironment in ARL cases and if so, define their function in that environment (Aim 3).

项目概要 HIV 感染者患非霍奇金淋巴瘤 (NHL) 的风险增加相关淋巴瘤 (ARL) 的起源被认为有两种主要机制。 ARL 的：1) EBV+ B 细胞免疫介导控制的丧失及其由于 T 细胞受损而发生的转化 HIV 疾病后期的细胞功能，以及 2) 慢性 B 细胞激活导致 DNA 修饰事件导致癌基因突变/易位，从而导致 B 细胞慢性激活和 T 细胞受损。我们和其他人已经证明，功能水平升高是淋巴瘤发生的重要因素。多种细胞因子（IL-6、IL-10、CXCL13、TNFα 和 IP-10/CXCL10）、与 B 细胞激活相关的分子（sCD23、sCD27、sCD30、κ 和 λ-免疫球蛋白游离轻链）和微生物易位因子（例如脂多糖结合蛋白（LPB）、sCD14、EndoCab）先于艾滋病相关 NHL 的发展 (ARL) 此外，B 调节细胞 (Bregs) (CD19+CD24+CD38+)，也表达程序性死亡- 配体 1 (PD-L1) 和分泌 IL-10 在 HIV 阳性个体的外周血中显着升高因此，炎症和微生物移位先于 ARL 的发生，并发挥着重要作用。最近，一种新的 CD4+ 辅助 T 细胞群被描述。 (CXCR5-CXCR3+PD-1hi CD4+)，已被命名为外周T辅助细胞(TPH)。据报道，存在于类风湿性关节炎和系统性狼疮的血液和慢性发炎的外周组织中红斑病患者的 TPH 细胞具有 B 细胞激活能力并分泌 IL-10。 HIV期间细胞因炎症和微生物易位而在外周组织中积聚感染同时诱导B细胞激活，并在肿瘤微环境的发育和维持中发挥作用，因此，在这项研究中，我们将测试是否会导致淋巴瘤发生和肿瘤生长以及 B 细胞功能障碍。这一假设是通过确定是否：1) 从 HIV 阳性和阴性个体中分离出的 TPH 细胞诱导 B 细胞激活和/或分化，和/或诱导已知与相关的Breg细胞标记物的表达 ARL 风险（目标 1）；如果 2) 免疫激活相关炎症和/或微生物易位有影响 TPH 细胞的产生（目标 2）；并且如果 3) TPH 细胞构成 ARL 病例中肿瘤微环境的一部分如果是，请定义其在该环境中的功能（目标 3）。