Immune checkpoints in the CNS and HIV-associated neurocognitive disorder

中枢神经系统和艾滋病毒相关神经认知障碍中的免疫检查点

• 批准号: 10889463
• 负责人: Yunlong Liu
• 金额: $ 82.37万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10889463
• 关键词: Address; Affect; Alternative Splicing; Astrocytes; Bar Codes; Binding; Biological; Biological Markers; Biological Process; Biological Response Modifiers; Brain; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; CTLA4 gene; Cell Line; Cells; Central Nervous System; Cerebrospinal Fluid; Circulation; Clinical; DNA; Data; Detection; Enzyme-Linked Immunosorbent Assay; Exhibits; Frequencies; Gene Expression Profile; Genes; Growth Factor; HIV; HIV Seronegativity; HIV-associated neurocognitive disorder; Hippocampus; Homeostasis; Human; Image; Immune; Immunity; Immunoassay; Immunohistochemistry; Immunoprecipitation; Individual; Inflammatory; Interferon Type II; Interleukin-1 beta; Lead; Ligands; Macaca mulatta; Macrophage; Malignant Neoplasms; Measures; Membrane; Messenger RNA; Microglia; Neuroimmune system; Neurologic Symptoms; Neurons; Neuropathogenesis; Pathogenesis; Pathway interactions; Peripheral; Persons; Production; Protein Isoforms; Protein Secretion; Proteins; RNA Splicing; Regulation; Reporting; Repression; Research; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Role; SIV; Sampling; Self Tolerance; Severities; Signal Transduction; T cell regulation; TNF gene; Tail; Techniques; Testing; Time; Tissue Sample; Tissues; Variant; Virus Diseases; antibody conjugate; brain cell; brain tissue; cancer cell; cell type; checkpoint receptors; chemokine; clinically relevant; cytokine; digital imaging; frontal lobe; immune cell infiltrate; immune checkpoint; in vivo; indexing; innovation; insight; melanoma; migration; monocyte; multiplex assay; neurocognitive disorder; neuroinflammation; peripheral blood; programmed cell death ligand 1; programmed cell death protein 1; receptor; single nucleus RNA-sequencing; spatial relationship; tumor

Abstract Immune checkpoints (ICPs) exert inhibitory or stimulatory effects on immune defense, surveillance, regulation, and self-tolerance through their ligand-receptor interactions. ICPs exist in both membrane-bound and soluble forms in vivo. Imbalances between inhibitory and stimulatory membrane-bound ICPs (mICPs) in malignant cells and immune cells in the peripheral blood and tissues have been well documented. Blockade of inhibitory mICPs such as CTLA-4, PD-1, and PD-L1 has become a revolutionary treatment for advanced stages of malignancies such as melanoma. However, the origin, regulation, and biological significance of both mICPs and soluble ICPs (sICPs) in the central nervous system (CNS) have not yet been systematically studied. We used a multiplex immunoassay to simultaneously quantify the concentrations of 16 sICPs in cerebrospinal fluid (CSF) samples from 33 HIV-negative individuals (HNIs) and 105 people living with HIV (PLWH), including 80 cases with HIV-associated neurocognitive disorder (HAND) and 25 cases without HAND. We found that 10 sICPs (sHVEM, sCD27, sGITR, sICOS, sLAG-3, sPD-1, sTIM-3, sBTLA, sCD28, & sCD40) were consistently detected in all CSF samples, and most of them were highly elevated in PLWH. Strikingly, CSF sHVEM was significantly increased in HAND when compared to PLWH without HAND. These 10 sICPs were also detectable in the CSF samples from rhesus macaques (RMs). Immunohistochemistry (IHC) analysis of brain tissues (frontal cortex and hippocampus) from RMs with and without simian immunodeficiency virus (SIV) infection showed that mHVEM was expressed at a basal level on neurons, but not on astrocytes or microglia, and mHVEM expression was highly increased in SIV-infected RMs (SIV/RMs). Furthermore, we have recently reported that PD-L1 expression in U87MG cells (a human astrocyte cell line) can be robustly induced by a mixture of IFN-γ/IL-1β/TNF-α, and induced PD-L1 controls production of MCP-1 (the most important chemokine that regulates migration of monocytes/macrophages) via PD-L1 intrinsic signaling. Thus, we hypothesize that both sICPs and mICPs are dysregulated in the CNS of PLWH, which are associated with HAND neuropathogenesis. We have two Specific Aims to test this central hypothesis: (1) To determine sICP profiles and biological functions in the CNS of PLWH and SIV/RMs, and (2) To characterize the cellular niches and spatial associations of ICP receptor/ligand-positive neural cells and infiltrating immune cells in the brain of PLWH and SIV/RMs. Our results will provide insights into the roles of ICPs in the CNS neuroimmune dysregulation and neuroinflammation of PLHIV with and without HAND. The CSF levels and profiles of sICPs such as sHVEM can potentially be used as a biomarker for HAND severity and progression.

摘要