Mechanisms for depleting tumor immunity in AIDS

描述（由申请人提供）：人类V?2V？T细胞对低分子量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性。表达这种T细胞受体的细胞在HIV疾病早期被耗尽，它们的丢失与艾滋病恶性疾病和机会性感染的风险增加有关。最近，我们报道（Alexander et al., 2008） ？？表达细胞表面CD56的T细胞对鳞状细胞癌细胞系具有强大的细胞毒性并抵抗TNF？或fas介导的细胞凋亡。CD56受Runx1转录因子调控，受common ？链细胞因子，可能反映了STAT 5的激活将释放Runx1进行核易位。细胞表面CD56在V?2V？2是一种共刺激受体，促进Akt-1的磷酸化和细胞凋亡抵抗。基于这些和其他数据，我们提出了一个控制？？T细胞水平：CD56的表达和细胞凋亡抵抗表型有利于循环人群中抗原经历细胞的积累，CD56的高表达与较高的基线V?2V？2水平。在HIV疾病中，有特定的V?2V？2+细胞被认为是通过间接机制发生的，因为细胞不表达CD4，并且在体外不容易感染HIV。迄今为止，耗竭的机制尚不清楚。我们最近的研究揭示了这些V?2V？在HIV+个体（集中于CD4 T细胞/mm3的供体）中仍有2个细胞，包括细胞因子刺激后表达CD56的能力显著下降。没有CD56，我们预测Akt-1磷酸化降低和凋亡敏感表型。在HIV感染的凋亡前环境中，敏感细胞会更快地被耗尽。这是一个合理且可测试的V?2V？2个细胞。我们的提案定义了V?2V？2细胞活化和抗凋亡表型的表达，并将这些机制与对照细胞和HIV+供体细胞进行比较。对照细胞被操纵以模仿来自HIV供体的细胞的行为，并且HIV供体细胞被改变以增加CD56表达和凋亡抵抗。特异性细胞因子或替代共刺激分子取代CD56和IL-2，以寻找激活和潜在地重建V?2V？HIV+个体中有2个细胞。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，可以降低Akt-1的激活，并可能降低细胞的凋亡抗性。T细胞。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。公共卫生相关性：在HIV感染期间，在CD4+细胞的情况下，T淋巴细胞在直接病毒感染后被耗尽，并且通过间接手段对其他不表达病毒受体的细胞。我们的研究集中在cd4阴性的？？T细胞在HIV疾病早期被耗尽，它们的损失降低了对癌症和传染病的天然免疫力。这项研究调查了控制细胞功能的细胞内信号通路，以发现与HIV感染相关的缺陷。了解这些缺陷并潜在地了解导致这些缺陷的病毒蛋白，是设计新的治疗方法来恢复的最接近的方法。HIV患者体内的T细胞。

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.