The role of dendritic cell subsets in cross-presentation and stimulation of homing marker expression

Topical antigen (Ag) application mimics natural Ag exposure across the skin. Soluble Ag introduced through this route requires cross-presentation by dendritic cells (DCs) to generate CD8 T cell responses, including skin-homing T cells. DCs process Ag for display to other immune cells, and stimulate T cells to release cytokines or directly lyse infected cells. Some T cells are further stimulated to express homing markers allowing them to enter non-lymphoid tissue such as the skin or the gut. In the last decade, DCs have been divided into subsets based on differential surface marker expression. The differences in development and function of these DC subsets are an area of active investigation. Some subsets may specialize in cross-priming T cells or imprinting skin homing, for example. Determining how different DC subsets interact with T cells would inform vaccine design and potentially lead to the development of DC-targeted vaccines. The studies described in this dissertation were undertaken to determine the contribution of various skin-derived DC subsets to cross-priming and skin-selective imprinting. We developed a co-culture system where DCs loaded in vivo with soluble Ag from skin could be isolated and used to stimulate T cell proliferation and homing marker expression in vitro. Using this co-culture system, we found that CD11b + MHCIIhi migratory DCs are responsible for the cross-presentation of soluble OVA protein Ag applied to skin. Both Langerin+ and Langerin- CD11b+ migratory DCs cross-present Ag, but only the Langerin+ subset can imprint the skin-selective homing marker E-selectin ligand on proliferating CD8 T cells. From these data, we conclude that the ability of skin-derived DCs to stimulate proliferation varies greatly and DCs that can stimulate proliferation do not necessarily imprint homing markers. Our findings significantly advance our understanding of the cell population responsible for producing skin-homing T cells and provide a possible target for vaccines targeting skin-applied Ag or skin-specific immune responses. We also identified a previously unknown role for CCR4 in DC subset development, opening the door for further research into the role of chemokine receptors in DC development and subsequent T cell stimulation capacity.