Regulation of CD8 T Cell Sensitivity to Adenosine A2a Receptor (A2aR) Signaling and Its Impact on CD8 T cell Tumor Control
Vincent, Isaah Saang, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia
Engelhard, Victor, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia
Adenosine and the adenosine A2a receptor (A2aR) work to promote tissue protection by inhibiting immune activation. Previous studies indicated that A2aR signaling inhibits T cell activation and production of inflammatory cytokines. However, these previous reports demonstrate incomplete blockade of CD8 T cell function. We hypothesize that this incomplete blockade is due to an A2aR agonist insensitive/A2aR signaling insensitive CD8 T cell population. Data presented within this thesis demonstrate that there are at least two subpopulations of CD8 T cells that differ in sensitivity to A2aR signaling and that the modulation of the proportion of cells that are sensitive to A2aR signaling can occur by at least two mechanisms. First, low expression of Gas in subpopulations of freshly isolated and effector CD8 T cells leads to reduced cAMP in response to A2aR agonists. Second, both culture of CD8 T cells in the presence of IL-12 during their differentiation or differentiation in response to vaccinia virus infection decreases the A2aR signaling sensitivity of effector CD8 T cells. IL-12 mediates this decreased sensitivity to A2aR signaling/cAMP by decreasing cAMP- mediated inhibition of TCR signaling. It has been previously demonstrated that A2aR expression inhibits tumor control. The impact of A2aR signaling on cells that mediate tumor control has not been adequately addressed. As CD8 T cells are an essential part of the anti-tumor immune response, the expression of the A2aR on these cells may inhibit their ability to control tumor. Effector CD8 T cells differentiated by antigen-presenting cells in tumor-bearing mice or mice immunized with soluble peptide are A2aR signaling sensitive. In a tumorbearing mouse, the A2aR expressed on these T cells inhibits their ability to control tumor iii outgrowth of B16 melanoma (B16) and Lewis Lung Carcinoma (LLC). This decreased tumor control is associated with decreased accumulation in the tumor of A2aR wild-type CD8 effector T cells and their enhanced apoptosis in the tumor-draining lymph node. Utilization of the subpopulation of A2aR agonist-resistant CD8 T cells or pharmacological blockade of A2aR signaling in CD8 T cells can potentially offer strategies to boost tumor immunotherapy aimed at generating tumor-specific CD8 T cells.
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PHD (Doctor of Philosophy)
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