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

• 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
• 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' 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' 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

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).

项目摘要 HIV感染者患非霍奇金淋巴瘤（NHL）的风险增加。几乎所有的艾滋病- 相关淋巴瘤（ARL）是B细胞起源的。两个主要的机制被认为有助于起源 1）由于受损的T-淋巴细胞的免疫介导的EBV+ B细胞控制及其转化的丧失， 细胞功能在HIV疾病的后期，和2）慢性B细胞活化导致DNA修饰事件 导致癌基因突变/易位。因此，慢性B细胞活化和受损的T细胞 功能是淋巴瘤发生的重要因素。我们和其他人已经证明， 几种细胞因子（IL-6、IL-10、CXCL 13、TNFα和IP-10/CXCL 10），与B细胞活化相关的分子 （sCD 23、sCD 27、sCD 30、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），sCD 14，EndoCab）先于艾滋病相关NHL的发展 （ARL）.此外，也表达程序性死亡的B调节细胞（BmT）（CD 19 + CD 24 + CD 38+）， 配体1（PD-L1）和分泌IL-10在HIV阳性个体的外周血中显著升高， 发展ARL。因此，炎症和微生物易位先于ARL的发展，并在ARL的发生发展中起重要作用。 在淋巴瘤发生中起重要作用。最近，人们描述了一种新型的CD 4+辅助性T细胞群体 （CXCR 5-CXCR 3 +PD-1hi CD 4+），其已被命名为外周辅助性T细胞（TPH）。TPH细胞已经被 据报道，在类风湿性关节炎和系统性狼疮的血液和慢性炎症外周组织中存在 红斑患者TPH细胞具有B细胞活化能力并分泌IL-10。我们假设TPH HIV感染期间，炎症和微生物易位导致细胞在外周组织中积聚， 感染，同时诱导B细胞活化，并在肿瘤小生境的发展和维持中发挥作用， 从而导致淋巴瘤发生和肿瘤生长以及B细胞功能障碍。在这项研究中，我们将测试 1）从HIV阳性和阴性个体分离的TPH细胞诱导B细胞增殖， 活化和/或分化，和/或诱导已知与以下相关的布雷格细胞标志物的表达： ARL风险（目的1）;如果2）免疫激活相关炎症和/或微生物易位导致 TPH细胞的产生（目的2）;以及3）TPH细胞是否构成ARL病例中肿瘤微环境的一部分 如果是，则定义它们在该环境中的功能（目标3）。