The role of CD4+CD8+ double-positive T-cell regulation of CD8 T-cell responses (2016-2018)

The presence of mature CD4+CD8+ Double-Positive (DP) T-cells in the gut, skin and peripheral lymphoid tissues has been described in numerous species and disease settings, including skin cancer. Recent evidence suggests that the emergence of CD4+CD8+ DP T-cells in the gut can be attributed to the transcriptional reprogramming of mature, single-positive T-cells following egress from the thymus. However, the function of CD4+CD8+ DP T-cells in the skin and skin-draining lymph node is largely unknown. Our preliminary work reveals that CD4+CD8beta+ DP T-cells are T-cell receptor-restricted and play a fundamental role in controlling CD8+ T-cell function in the skin. The principal goal of this proposal is to generate an in-depth understanding of the biology of CD4+CD8+ DP T-cells and dissect the mechanisms by which CD4+CD8+ DP T-cells act as central regulators of cutaneous CD8+ T-cell responses. The outcomes of this work will therefore provide fundamental understanding of this commonly overlooked or ignored fraction of T-cells and provide a route to determining the role of CD4+CD8¿¿+ DP T-cells in skin disease. HYPOTHESIS: We hypothesize that CD4+CD8+ DP T-cells play a critical role in the control of CD8+ T-cell function in the skin. AIMS: 1) Examine the relationship between different lineages of origin and the phenotype and function of CD4+CD8¿¿+ DP T-cells 2) Determine how CD4+CD8¿¿+ DP T-cells impact the function of CD8+ T-cells in vivo 3) Define the mechanism by which CD4+CD8¿¿+ DP T-cells modulate CD8+ T-cell function This proposal is highly innovative and will provide important new insights into a fundamental and novel mechanism for CD8 T-cell regulation. Ultimately, this work will expedite novel strategies designed to selectively enable or suppress cytotoxic CD8 T-cell function in the skin.