Mechanisms for depleting tumor immunity in AIDS

艾滋病中肿瘤免疫耗竭的机制

• 批准号: 8063017
• 负责人: C. David Pauza
• 金额: $ 49.83万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063017
• 关键词: AIDS therapy; Accounting; Acquired Immunodeficiency Syndrome; Address; Affect; Agonist; Antigens; Apoptosis; Apoptotic; B-Lymphocytes; Blood; CD4 Positive T Lymphocytes; Cell Cycle; Cell Line; Cell physiology; Cell surface; Cells; Communicable Diseases; Cytokine Signaling; Data; Defect; Diphosphates; Disease; Environment; Event; Exhibits; Failure; Goals; HIV; HIV Infections; Health; Human; Immune; Immune system; Immunologic Deficiency Syndromes; In Vitro; Individual; Interleukin-2; Knowledge; Laboratories; Lymphocyte; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Weight; NCAM1 gene; Natural Immunity; Natural Killer Cells; Nuclear Translocation; Opportunistic Infections; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Persons; Phenotype; Phosphorylation; Population; Proteins; Regulation; Reporting; Research; Resistance; Risk; Role; STAT5A gene; Signal Pathway; Signal Transduction; Squamous cell carcinoma; T-Cell Depletion; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Testing; Tumor Immunity; Viral; Viral Proteins; Virus Diseases; Virus Receptors; antiretroviral therapy; base; cell behavior; cytokine; cytotoxic; cytotoxicity; design; experience; innovation; isoprenoid; loss of function; microbial; nef Protein; pathogen; prevent; receptor; reconstitution; therapy design; transcription factor; tumor

DESCRIPTION (provided by applicant): Human V?2V?2 T cells respond to low molecular weight isoprenoid pyrophosphate antigens and exhibit cytotoxicity against a variety of human tumors. Cells expressing this T cell receptor are depleted early in HIV disease and their loss is associated with increased risk for malignant disease and opportunistic infections in AIDS. Recently, we reported (Alexander, et al., 2008) that the subset of ??T cells expressing cell surface CD56 is potently cytotoxic against squamous cell carcinoma cell lines and resists TNF? or Fas-mediated cellular apoptosis. CD56 is regulated by the Runx1 transcription factor and increases after stimulation by common ? chain cytokines, possibly reflecting STAT 5 activation that would free Runx1 for nuclear translocation. Cell surface CD56 on V?2V?2 was a costimulatory receptor, promoting phosphorylation of Akt-1 and apoptosis resistance. Based on these and additional data, we proposed a model for the control of ?? T cell levels: Expression of CD56 and the apoptosis resistance phenotype favored accumulation of antigen- experienced cells in the circulating population and higher expression of CD56 was associated with higher baseline V?2V?2 levels. In HIV disease, there is specific depletion of V?2V?2+ cells that is presumed to occur by indirect mechanisms because the cells do not express CD4 and are not susceptible to HIV infection in vitro. To date, the mechanism for depletion is not known. Our recent studies revealed phenotypic differences in those V?2V?2 cells remaining in HIV+ individuals (concentrating on donors with >300 CD4 T cells/mm3), including a significantly decreased capacity for expressing CD56 after cytokine stimulation. Without CD56 we predict lower Akt-1 phosphorylation and an apoptosis-sensitive phenotype. In the pre-apoptotic environment of HIV infection, sensitive cells would be depleted more rapidly. This is a plausible and testable model for the loss of V?2V?2 cells during HIV disease. Our proposal defines individual steps in the pathway for V?2V?2 cell activation and expression of the apoptosis-resistant phenotype and compares these mechanisms with cells from control and HIV+ donors. Control cells are manipulated to mimic the behavior of cells from HIV donors and HIV donor cells are altered to increase CD56 expression and apoptosis-resistance. Specific cytokines or alternate costimulatory molecules are substituted for CD56 and IL-2 to search for means to activate and potentially reconstitute V?2V?2 cells in HIV+ individuals. Recent studies implicated the Nef protein as an agonist for peroxisome proliferator activated receptor (PPAR) that would decrease Akt-1 activation and potentially decrease apoptosis-resistance in ???T cells. We will test Nef to determine whether this viral accessory protein has a role in the ??T cell depletion mechanism. PUBLIC HEALTH RELEVANCE: During HIV infection, T lymphocytes are depleted after direct virus infection, in the case of CD4+ cells, and by indirect means for other cells that do not express the virus receptor. Our studies focus on the CD4-negative ??T cells that are depleted early in HIV disease and their loss reduces natural immunity to cancer and infectious disease. The research investigates intracellular signaling pathways that control cell functions, to uncover defects associated with HIV infection. Knowledge of these defects and potentially understanding the viral proteins responsible for these defects, is proximal to designing new therapy approaches to recover ?? T cells in persons with HIV disease.

描述（由申请人提供）：人类V？2V？2个T细胞对低分子量异磷酸二磷酸抗原反应，并针对各种人类肿瘤表现出细胞毒性。表达该T细胞受体的细胞在HIV疾病的早期就会耗尽，其丧失与艾滋病中恶性疾病和机会性感染的风险增加有关。最近，我们报道（Alexander等，2008），表达细胞表面CD56的细胞的子集对鳞状细胞癌细胞系有效地细胞毒性并抵抗TNF？或FAS介导的细胞凋亡。 CD56受RUNX1转录因子的调节，并在共同刺激后增加吗？链细胞因子，可能反映了STAT 5激活，该激活将使Runx1释放用于核易位。 V？2V？2上的细胞表面CD56是共刺激受体，促进了Akt-1和抗凋亡耐药性的磷酸化。基于这些和其他数据，我们提出了一个控制？ T细胞水平：CD56的表达和凋亡耐药性表型有利于循环种群中抗原经验的细胞积累，CD56的较高表达与较高的基线V？2V？2水平有关。在HIV疾病中，V？2V？2+细胞的特异性耗竭是由于细胞不表达CD4并且在体外不易感HIV感染而被认为是通过间接机制发生的。迄今为止，尚不清楚耗尽的机制。我们最近的研究表明，在HIV+个体中剩下的那些V？2V？2个细胞（集中在> 300 CD4 T细胞/mm3的供体上）中的表型差异，包括在细胞因子刺激后表达CD56的能力大大降低。没有CD56，我们可以预测较低的AKT-1磷酸化和对凋亡敏感的表型。在艾滋病毒感染的凋亡前环境中，敏感细胞会更快地耗尽。这是一个合理且可检验的模型，用于在HIV疾病期间丧失V？2V？2细胞。我们的建议定义了V？2V？2细胞激活和抗凋亡表型的表达的各个步骤，并将这些机制与对照和HIV+供体的细胞进行比较。操纵对照细胞以模仿艾滋病毒供体细胞的行为，而艾滋病毒供体细胞被改变以增加CD56表达和凋亡耐药性。特定的细胞因子或替代共刺激分子被用CD56和IL-2取代，以寻找激活HIV+个体中的V？2V？2细胞的方法。最近的研究暗示了NEF蛋白是过氧化物酶体增殖物激活受体（PPAR）的激动剂，该激动剂会降低AKT-1激活并潜在地降低？T细胞中的凋亡抗性。我们将测试NEF，以确定该病毒辅助蛋白是否在细胞耗尽机制中起作用。公共卫生相关性：在艾滋病毒感染期间，在直接病毒感染（在CD4+细胞的情况下）以及其他不表达病毒受体的细胞的间接手段，T淋巴细胞耗尽。我们的研究集中于在艾滋病毒疾病早期耗尽的CD4阴性细胞，其损失降低了对癌症和传染病的自然免疫。该研究研究了控制细胞功能的细胞内信号传导途径，以发现与HIV感染相关的缺陷。对这些缺陷的了解以及可能了解负责这些缺陷的病毒蛋白，靠近设计恢复的新疗法方法？艾滋病毒疾病患者的T细胞。