Mechanisms for depleting tumor immunity in AIDS

人V <$2V <$2 T细胞对低分子量类异戊二烯焦磷酸抗原有应答， 针对多种人类肿瘤的细胞毒性。表达这种T细胞受体的细胞在HIV早期被耗尽 疾病及其损失与恶性疾病和机会性感染的风险增加有关， 艾滋病最近，我们报道了（亚历山大等人，2008），表达细胞表面的T细胞亚群 CD 56对鳞状细胞癌细胞系具有强效细胞毒性，并抵抗TNF或Fas介导的 细胞凋亡CD 56受Runx 1转录因子调节，并在受Runx 1刺激后增加。 常见的半链细胞因子，可能反映STAT 5激活，释放Runx 1用于细胞核 易位V <$2V <$2上的细胞表面CD 56是共刺激受体，促进Akt-1的磷酸化 和凋亡抗性。基于这些数据和其他数据，我们提出了一个控制T细胞的模型， 水平：CD 56的表达和凋亡抵抗表型有利于抗原的积累， 在循环群体中，CD 56的高表达与高表达相关。 基线V <$2V <$2水平。 在HIV疾病中，存在特异性的V <$2V <$2+细胞耗竭，推测其通过间接机制发生 因为这些细胞不表达CD 4，在体外不易受HIV感染。迄今为止，该机制 消耗是未知的。我们最近的研究揭示了这些V <$2V <$2细胞的表型差异， 在HIV+个体中（集中于具有>300个CD 4 T细胞/mm 3的供体），包括显著降低的 细胞因子刺激后表达CD 56的能力。没有CD 56，我们预测Akt-1磷酸化较低 和一种对乳腺癌敏感的表型。在HIV感染的凋亡前环境中，敏感细胞将 更快地被耗尽。这是一个合理的和可测试的模型，用于HIV感染过程中V <$2V <$2细胞的丢失。 疾病 我们的建议定义了V <$2V <$2 T细胞活化和表达V2 V <$2 T细胞的途径中的各个步骤。 艾滋病耐药表型，并比较这些机制与控制和HIV+捐助者的细胞。 操纵对照细胞以模拟来自HIV供体的细胞的行为，并且改变HIV供体细胞以 增加CD 56表达和抗肿瘤作用。特异性细胞因子或交替共刺激分子 取代CD 56和IL-2，以寻找激活和潜在重建V2 V2细胞的方法， 艾滋病毒阳性者。最近的研究暗示Nef蛋白作为过氧化物酶体增殖物激活的激动剂， 受体（PPAR），这将减少Akt-1的激活，并可能降低糖尿病患者的耐受性。 细胞我们将测试Nef，以确定这种病毒辅助蛋白是否在T细胞耗竭中发挥作用。 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.