Immunity to Virus-induced Tumors

描述(申请人提供)：病毒是引发癌症的致病因素。CD8 T细胞的持续监测控制着肿瘤的生长。最佳的CD8 T细胞反应需要CD4T细胞的帮助。在T细胞的细胞因子分泌模式中可以看到一种广义的二分法，称为Th1和Th2。这些细胞因子与CD8 T细胞功能相互作用的结果尚不完全清楚，但可能具有相反的功能效应。小鼠是多瘤病毒的天然宿主，多瘤病毒是一种致癌的DNA病毒。最近的研究表明，CD94/NKG2A受体阻断了多发性肿瘤特异性CD8T细胞的裂解活性。细胞因子和/或抗原可以控制这种抑制性受体的表达。初步研究表明，来自肿瘤易感性的T细胞产生IL-4。因此，我们假设，主要的Th2CD4T细胞反应通过调节抑制性受体CD94/NKG2a，对多发性肿瘤特异性CD8T细胞的裂解活性产生负面影响。目的：研究CD94/NKG2A对肿瘤耐药小鼠和肿瘤易感小鼠的影响，了解CD94/NKG2A的调控因素。CD4T细胞的细胞因子表达谱将使用ELISPOTS进行定量。将表达不同水平CD94/NKG2A的多瘤特异性CD8T细胞转移到未感染的动物或感染了抗原性无关病毒的动物体内。将在宿主动物中监测CD94/NKG2A的表达和功能，以确定该受体上调和功能的要求。这些研究将阐明这一角色。多种因素在产生和维持强大的抗肿瘤CD8T细胞中发挥作用。这些信息可以帮助开发治疗干预措施，以刺激CD8T细胞根除癌症。

DESCRIPTION (provided by applicant): Viruses are causative factors in cancer initiation. Constant surveillance by CD8 T cells controls the outgrowth of tumors. Optimal CD8 T cell responses require help from CD4 T cells. A generalized dichotomy can be seen in cytokine secretion patterns from T cells, termed Th1 and Th2. The outcomes of the interactions of these cytokines with CD8 T cell functions are not completely understood, but may have opposing functional effects. The mouse is a natural host for polyoma virus, an oncogenic DNA virus. Recently, it was shown that the CD94/NKG2A receptor blocks the lytic activity of polyoma-specific CD8 T cells. Cytokines and/or antigen, may control expression of this inhibitory receptor. Preliminary studies indicate that T cells from tumor-susceptible produce IL-4. Therefore, we hypothesize that a dominant Th2 CD4 T cell response negatively impacts on the lytic activity of polyoma-specific CD8 T cells through modulation of the inhibitory receptor, CD94/NKG2A. Specific aims: To determine the impact CD4 T cells and their cytokine secretion profiles in tumor-resistant and tumor-susceptible mice; to understand factors controlling the regulation of CD94/NKG2A. Cytokine expression profiles of CD4 T cells will be quantitated using Elispots. Transfer of polyoma-specific CD8 T cells, which express different levels of CD94/NKG2A, into uninfected animals or animals infected with an antigenically irrelevant virus will be done. CD94/NKG2A expression and function will be monitored in the host animals to determine requirements for upregulation and function of this receptor. These studies will elucidate the role. Various factors play in the generation and maintenance of potent anti-tumor CD8 T cells. This information can aid in the development of therapeutic interventions to stimulate CD8 T cells for cancer eradication.