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).

项目总结 艾滋病毒感染者罹患非霍奇金淋巴瘤(NHL)的风险增加。几乎所有的艾滋病人- 相关性淋巴瘤(ARL)起源于B细胞。两种主要机制被认为是导致这种疾病发生的原因。 ARL：1)T细胞受损导致EBV+B细胞失去免疫调节及其转化。 HIV疾病后期的细胞功能，以及2)导致DNA修饰事件的慢性B细胞激活 导致癌基因突变/易位的基因。因此，慢性B细胞激活和T细胞受损 功能是淋巴肿大的重要因素。我们和其他人已经证明，高水平的 几种与B细胞活化相关的细胞因子(IL-6、IL-10、CXCL13、肿瘤坏死因子α和IP-10/CXCL10) (CD23、CD27、CD30、κ和λ-免疫球蛋白自由轻链)和微生物易位因子(如 脂多糖结合蛋白(LPB)、sCD14、EndoCab在艾滋病相关非霍奇金淋巴瘤发生发展中的作用 (ARL)。此外，B调节细胞(Bregs)(CD19+CD24+CD38+)也表达程序性死亡- HIV感染者外周血中配体1(PD-L1)和分泌IL-10显著升高 发展ARL。因此，炎症和微生物移位先于ARL的发生，在ARL的发病过程中起重要作用。 在淋巴增生症中起重要作用。最近，一种新的CD4+辅助T细胞群体被描述出来 (CXCR5-CXCR3+PD-1hi CD4+)，已命名为外周T辅助细胞(TPH)。TPH细胞已经被 类风湿性关节炎和系统性红斑狼疮的血液和慢性炎症外周组织中的报告 红斑狼疮患者。TPH细胞具有B细胞活化能力和分泌IL-10的能力。我们假设TPH HIV感染期间炎症和微生物移位导致细胞在周围组织中积聚 感染同时诱导B细胞激活，并在肿瘤生态位的发展和维持中发挥作用， 因此，有助于淋巴肿大和肿瘤生长，以及B细胞功能障碍。在这项研究中，我们将测试 这一假设通过确定：1)从HIV阳性和阴性个体分离的TPH细胞是否诱导B细胞 激活和/或分化，和/或诱导已知与以下因素相关的Breg细胞标志物的表达 ARL的风险(目标1)；如果2)免疫激活相关的炎症和/或微生物易位 对于TPH细胞的产生(目标2)；以及如果3)在ARL病例中TPH细胞构成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)。