Mechanisms for depleting tumor immunity in AIDS

人V？2V？2T细胞对低分子量焦磷酸异戊二烯抗原的反应和表现 对多种人类肿瘤的细胞毒作用。表达这种T细胞受体的细胞在HIV早期就被耗尽了 疾病及其损失与恶性疾病和机会性感染的风险增加有关 艾滋病。最近，我们报道(Alexander，et al.，2008)表达细胞表面的T细胞亚群 CD56对鳞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介导的细胞毒作用 细胞凋亡。CD56受RUNX1转录因子调节，刺激后CD56增加 共同的链状细胞因子，可能反映了STAT5的激活，从而释放了RUNX1的核 易位。V2V2细胞表面CD56是共刺激受体，促进Akt-1的磷酸化 和抗细胞凋亡。基于这些数据和附加数据，我们提出了一个控制T细胞的模型 水平：CD56的表达和抗凋亡表型有利于抗原的积累- 循环人群中有经验的细胞和CD56的高表达与高水平相关 基线V？2V？2水平。 在HIV疾病中，存在V？2V？2+细胞的特异性耗竭，这被认为是通过间接机制发生的 因为这些细胞不表达CD4，在体外对HIV感染不敏感。到目前为止，该机制 因为耗尽是未知的。我们最近的研究揭示了剩下的V？2V？2细胞的表型差异 在HIV+个体中(集中在&gt；300 CD4T细胞/mm3的捐赠者)，包括显著降低的 细胞因子刺激后表达CD56的能力。如果没有CD56，我们预测Akt-1的磷酸化程度会降低 和一种对细胞凋亡敏感的表型。在艾滋病毒感染的前凋亡环境中，敏感细胞将 会更快地耗尽。这是一个在HIV期间V？2V？2细胞丢失的可信和可测试的模型 疾病。 我们的方案定义了V？2V？2T细胞活化和表达的各个步骤 并将这些机制与来自对照和HIV+捐赠者的细胞进行比较。 控制细胞被操纵以模仿来自艾滋病毒捐赠者的细胞的行为，而艾滋病毒捐赠者细胞被改变为 增加CD56的表达和抗凋亡作用。特定的细胞因子或交替的共刺激分子 取代CD56和IL-2以寻找激活和潜在重建V？2V？2细胞的方法 HIV+的个人。最近的研究表明Nef蛋白是过氧化物酶体增殖物激活的激动剂 受体(PPAR)将降低Akt-1的激活并潜在地降低T细胞的凋亡抵抗 细胞。我们将测试Nef以确定这种病毒辅助蛋白是否在T细胞耗尽中起作用 机制。

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.