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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：
9751059
负责人：
Marta Epeldegui
金额：
$ 31.56万
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：
2019-08-09 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751059
关键词：
AIDS-Related Lymphoma AIDS-Related Non-Hodgkin&apos s Lymphoma Acquired Immunodeficiency Syndrome Automobile Driving B-Cell Activation B-Cell Lymphomas B-Cell Neoplasm B-Lymphocytes BCL1 Oncogene BLR1 gene Blood Circulation CD8-Positive T-Lymphocytes CD8B1 gene CXCL13 gene Cell Communication Cell Culture Techniques Cell Proliferation Cell Survival Cell physiology Cells Chronic Coculture Techniques Cytometry Cytotoxic T-Lymphocytes DNA Development Diagnosis Disease Disease Progression Environment Event Functional disorder Generations Genetic Transcription Growth Gut associated lymphoid tissue HIV HIV Infections HIV Seronegativity Helper-Inducer T-Lymphocyte Human Herpesvirus 4 IL6 gene Image Immune Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin Genes Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Impairment Individual Inflammation Inflammatory Interferon Type II Interleukin-10 Lymphocytic choriomeningitis virus Lymphoid Lymphoid Tissue Lymphoma Lymphomagenesis Maintenance Malignant Neoplasms Measures Memory Modeling Molecular Mutation Non-Hodgkin&apos s Lymphoma Oncogenes Oncogenic PDCD1LG1 gene Pathogenesis Persons Plasma Cells Play Population Production Risk Role SLEB2 gene Site Structure of germinal center of lymph node T-Lymphocyte TNF gene TNFRSF5 gene TNFSF5 gene Testing Tissues Tumor Subtype Virion Virus Diseases activation-induced cytidine deaminase cytokine exhaust exhaustion immune activation immunoregulation infected B cell interleukin-21 lymph nodes microbial mouse model neoplastic cell novel peripheral blood receptor tumor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY HIV infection is associated with a greatly increased risk for the development of non-Hodgkin lymphoma (NHL). Nearly all AIDS-related lymphomas (ARL) are of B cell origin. Two major mechanisms are believed to contribute to the genesis of ARL: 1) loss of immunoregulation of EBV+ B cells resulting from 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. Therefore, both chronic B cell activation and impaired CD8 T cell function are important contributors to lymphomagenesis. Recently, two different groups described a subpopulation of CD8+ T cells that expresses CXCR5 (the receptor for CXCL13) in the LCMV model, a mouse model of chronic viral infection. In these studies, this novel population of CD8+CXCR5+ T cells, also called follicular CD8 (fCD8+) T cells, were shown to express PD1, and were seen to be LCMV-specific and located in secondary lymphoid tissues. Additionally, fCD8+ T cells were recently shown to be present in tumors and to promote B cell activation. Moreover, large numbers of fCD8+ T cells have been observed in a lymphoma mouse model. Inflammation and immune activation may be responsible for driving the accumulation of fCD8+ T cells in the B cell follicles, since there is an accumulation of inflammatory cells and CXCL13 in lymph nodes of HIV+ individuals. Since inflammation and microbial translocation precede ARL development and play an important role in lymphomagenesis, it is reasonable to think that inflammation and microbial translocation may be important in the accumulation of fCD8+ T cells in HIV infection. fCD8+ T cells may also play a role in the development and maintenance of the tumor niche. Together, this had led us to hypothesize that fCD8+ T cells, which are known to be elevated in HIV infection, result from inflammation/microbial translocation, are part of the tumor niche, and induce B cell activation contributing to lymphomagenesis and tumor growth, as well as B cell dysfunction. In this study, we will test this hypothesis by determining if: 1) fCD8+ T cells from HIV-negative and HIV+ individuals induce B cell activation and/or Breg cells, both present prior to ARL diagnosis (aim 1), 2) immune activation-associated inflammation and/or microbial translocation contribute to the generation of fCD8+ T cells and if fCD8+ T cells are present in gut associated lymphoid tissue in HIV+ individuals, the site where microbial translocation/inflammation take place (aim 2), and 3) fCD8+ T cells function as part of the tumor micro-environment in ARLs and defining how they may be contributing to tumor development (aim 3).

项目摘要 HIV感染与非霍奇金淋巴瘤（NHL）发展的风险大大增加有关。几乎所有的艾滋病相关淋巴瘤（ARL）是B细胞起源。据信有两种主要机制有助于ARL的发生：1）由受损的T细胞引起的EBV+ B细胞的免疫调节丧失在HIV疾病的后期发挥作用，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CD 8 T细胞都可能是一种免疫抑制剂。细胞功能是淋巴瘤发生的重要因素。最近，两个不同的团体描述了一个在LCMV模型中表达CXCR 5（CXCL 13的受体）的CD 8 + T细胞亚群，慢性病毒感染的模型。在这些研究中，这种新的CD 8 + CXCR 5 + T细胞群体，也被称为滤泡性CD 8（fCD 8+）T细胞显示表达PD 1，并且被认为是LCMV特异性的，位于LCMV的淋巴细胞中。次级淋巴组织此外，最近显示fCD 8 + T细胞存在于肿瘤中，促进B细胞活化。此外，在淋巴瘤中观察到大量fCD 8 + T细胞，小鼠模型炎症和免疫激活可能是驱动fCD 8+积聚的原因。 B细胞滤泡中的T细胞，因为淋巴结中存在炎性细胞和CXCL 13的积累 HIV+的人。由于炎症和微生物易位先于ARL的发展，在淋巴瘤发生中起重要作用，因此认为炎症和微生物易位可能在HIV感染中fCD 8 + T细胞的积累中很重要。fCD 8 + T细胞也可能在免疫应答中发挥作用。肿瘤生态位的发展和维持。总之，这使我们假设fCD 8 + T细胞，已知其在HIV感染中升高，由炎症/微生物易位引起，是肿瘤小生境，并诱导有助于淋巴瘤生成和肿瘤生长的B细胞活化，以及B细胞活化。细胞功能障碍在这项研究中，我们将通过确定以下情况来检验这一假设：1）来自HIV阴性的FCD 8 + T细胞，和HIV+个体诱导B细胞活化和/或布雷格细胞，两者均在ARL诊断之前存在（目的1），2）免疫激活相关炎症和/或微生物易位有助于fCD 8+的产生如果fCD 8 + T细胞存在于HIV+个体的肠道相关淋巴组织中，则在HIV+个体中，发生微生物易位/炎症（目的2），3）fCD 8 + T细胞作为肿瘤的一部分发挥作用 ARL中的微环境，并确定它们如何促进肿瘤发展（目的3）。