Mechanisms for depleting tumor immunity in AIDS

艾滋病中肿瘤免疫耗竭的机制

基本信息

批准号：
8254371
负责人：
C. David Pauza
金额：
$ 30.19万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8254371
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 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 Activation 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

项目摘要

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 T 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.

人类V¿ 2V?? 2 T 细胞对低分子量类异戊二烯焦磷酸抗原作出反应并表现出表达这种 T 细胞受体的细胞在 HIV 早期就被耗尽。疾病及其损失与恶性疾病和机会性感染的风险增加有关最近，我们报道（Alexander 等人，2008），¿ ¿表达细胞表面的 T 细胞 CD56 对鳞状细胞癌细胞系具有强效细胞毒性，并能抵抗 TNF¿或Fas介导的 CD56 受 Runx1 转录因子调节，并在受到刺激后增加。常见的链细胞因子，可能反映了 STAT 5 的激活，该激活将释放 Runx1 进入核 V¿ 上的细胞表面 CD56 2V?? 2是共刺激受体，促进Akt-1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 的表达和细胞凋亡抗性表型有利于抗原积累循环细胞群中经历过的细胞和 CD56 的较高表达与较高的基线 V¿ 2V?? 2 级。在 HIV 疾病中，V 存在特异性缺失2V??推测通过间接机制发生的 2+ 细胞因为这些细胞不表达CD4，在体外不易受到HIV感染。我们最近的研究揭示了这些 V 的表型差异。 2V??剩余 2 格 HIV+ 个体（集中于 CD4 T 细胞/mm3 > 300 个的捐赠者），包括显着下降细胞因子刺激后表达 CD56 的能力，如果没有 CD56，我们预测 Akt-1 磷酸化会降低。在HIV感染的凋亡前环境中，敏感细胞会出现凋亡敏感表型。这是一个关于 V 损失的合理且可测试的模型。 2V?? HIV期间2个细胞疾病。我们的提案定义了 V¿ 路径中的各个步骤2V?? 2 T细胞的激活和表达细胞凋亡抵抗表型，并将这些机制与来自对照和 HIV+ 供体的细胞进行比较。对照细胞被操纵以模仿 HIV 供体细胞的行为，而 HIV 供体细胞将增加 CD56 表达和细胞凋亡抗性。替代 CD56 和 IL-2，以寻找激活和潜在重建 V 的方法？ 2V?? 2 个细胞最近的研究表明 Nef 蛋白是激活过氧化物酶体增殖物的激动剂。受体 (PPAR) 会降低 Akt-1 的激活并可能降低 ¿ ¿时间我们将测试 Nef 以确定这种病毒辅助蛋白是否在 ¿ ¿ T细胞耗竭机制。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rapamycin increases the yield and effector function of human γδ T cells stimulated in vitro.

DOI：
10.1007/s00262-010-0945-7
发表时间：
2011-03
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
0
作者：
Li H;Pauza CD
通讯作者：
Pauza CD

Critical roles for Akt kinase in controlling HIV envelope-mediated depletion of CD4 T cells.

DOI：
10.1186/1742-4690-10-60
发表时间：
2013-06-06
期刊：
Retrovirology
影响因子：
3.3
作者：
Li H;Pauza CD
通讯作者：
Pauza CD

High affinity allele for the gene of FCGR3A is risk factor for HIV infection and progression.

DOI：
10.1371/journal.pone.0015562
发表时间：
2010-12-20
期刊：
PloS one
影响因子：
3.7
作者：
Poonia B;Kijak GH;Pauza CD
通讯作者：
Pauza CD

Reply to Hartjen et al.

回复 Hartjen 等人。

DOI：
10.1093/infdis/jit142
发表时间：
2013
期刊：
The Journal of infectious diseases
影响因子：
0
作者：
Boudova,Sarah;Li,Haishan;Sajadi,MohammadM;Redfield,RobertR;Cairo,Cristiana;DavidPauza,C
通讯作者：
DavidPauza,C

Evolution and function of the TCR Vgamma9 chain repertoire: It's good to be public.

TCR Vgamma9 链库的演变和功能：公开是件好事。