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(申请人提供)：人类V？2V？2T细胞对低分子量的类异戊二烯焦磷酸抗原有反应，并对多种人类肿瘤表现出细胞毒作用。表达这种T细胞受体的细胞在HIV疾病早期就被耗尽，它们的丢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(Alexander，et al.，2008)报道，表达细胞表面CD56的T细胞亚群对鳞状细胞癌细胞株具有很强的细胞毒作用，并能抵抗肿瘤坏死因子？或Fas介导的细胞凋亡。CD56受RUNX1转录因子调控，受普通？链状细胞因子，可能反映STAT5的激活，从而释放RUNX1进行核转位。V2V2细胞表面CD56是一种共刺激受体，促进Akt-1的磷酸化和抗凋亡作用。基于这些数据和补充数据，我们提出了一个控制？？T细胞水平：CD56的表达和抗凋亡表型有利于抗原感受细胞在循环人群中的聚集，CD56的高表达与基础V 2V2水平的升高相关。在HIV疾病中，V、2V、2+细胞的特异性耗竭可能是通过间接机制发生的，因为这些细胞不表达CD4并且在体外对HIV感染不敏感。到目前为止，耗尽的机制尚不清楚。我们最近的研究揭示了HIV+个体(集中在拥有300个CD4T细胞/mm3的捐赠者)中残留的V？2V？2细胞的表型差异，包括细胞因子刺激后表达CD56的能力显著降低。如果没有CD56，我们预测Akt-1的磷酸化程度较低，并出现对凋亡敏感的表型。在艾滋病毒感染的前凋亡环境中，敏感细胞会更快地耗尽。这是一种可信的、可检验的在HIV疾病过程中V？2V？2细胞丢失的模型。我们的建议定义了V？2V？2细胞激活和抗凋亡表型表达途径中的各个步骤，并将这些机制与对照组和HIV+捐赠者的细胞进行了比较。对照细胞被操纵来模仿来自HIV捐赠者的细胞的行为，而HIV捐赠者细胞被改变以增加CD56的表达和抗凋亡能力。用特定的细胞因子或交替的共刺激分子来替代CD56和IL-2，以寻找激活和潜在地重建HIV+患者V？2V？2细胞的方法。最近的研究表明，Nef蛋白是过氧化物酶体增殖物激活受体(PPAR)的激动剂，可降低Akt-1的活性，并潜在地降低T细胞的抗凋亡能力。我们将测试Nef以确定这种病毒辅助蛋白是否在T细胞耗尽机制中发挥作用。公共卫生相关性：在艾滋病毒感染期间，T淋巴细胞在病毒直接感染后被耗尽，在CD4+细胞的情况下，并通过间接方式对不表达病毒受体的其他细胞。我们的研究集中在HIV疾病早期耗尽的CD4阴性T细胞，它们的丢失降低了对癌症和传染病的自然免疫力。这项研究调查了控制细胞功能的细胞内信号通路，以揭示与艾滋病毒感染相关的缺陷。了解这些缺陷并可能了解导致这些缺陷的病毒蛋白，是否接近设计新的治疗方法来恢复？HIV感染者体内的T细胞。