Immunity to Virus-induced Tumors

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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.