Immunity to Virus-induced Tumors

描述（由申请方提供）：病毒是癌症发生的致病因素。CD 8 T细胞的持续监视控制着肿瘤的生长。最佳的CD 8 T细胞应答需要CD 4 T细胞的帮助。在T细胞的细胞因子分泌模式中可以看到广义的二分法，称为Th 1和Th 2。这些细胞因子与CD 8 T细胞功能相互作用的结果尚未完全了解，但可能具有相反的功能效应。小鼠是多瘤病毒（一种致癌DNA病毒）的天然宿主。最近，研究表明，CD 94/NKG 2A受体阻断多瘤特异性CD 8 T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，我们假设显性Th 2 CD 4 T细胞应答通过调节抑制性受体CD 94/NKG 2A对多瘤特异性CD 8 T细胞的裂解活性产生负面影响。具体目标：确定CD 4 T细胞及其细胞因子分泌谱在肿瘤耐药和肿瘤易感小鼠中的影响;了解控制CD 94/NKG 2A调节的因素。将使用Elispots定量CD 4 T细胞的细胞因子表达谱。将多瘤特异性CD 8 T细胞（表达不同水平的CD 94/NKG 2A）转移至未感染动物或感染抗原无关病毒的动物中。将在宿主动物中监测CD 94/NKG 2A表达和功能，以确定该受体上调和功能的要求。这些研究将阐明其作用。 多种因素在有效的抗肿瘤CD 8 T细胞的产生和维持中起作用。这些信息可以帮助开发治疗干预措施，以刺激CD 8 T细胞来根除癌症。

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.