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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：
10388429
负责人：
Marta Epeldegui
金额：
$ 11.79万
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/10388429
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 Lymphoma cell Lymphomagenesis Maintenance Malignant Neoplasms Measures Memory Modeling Molecular Mutation Non-Hodgkin&apos s Lymphoma Oncogenes Oncogenic Pathogenesis Persons Plasma Cells Play Population Production Risk Role 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 programmed cell death ligand 1 programmed cell death protein 1 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).

项目总结