Induction of gut homing T cells by systemic dendritic cells

Abstract

An effective vaccine against mucosal pathogens such as the Human Immunodeficiency Virus 1 (HIV-1) must provide immunity at the mucosal level. Understanding the ability of mucosal dendritic cells (DCs) to induce gut homing lymphocytes plays a crucial parameter in the development of vaccines that mount a specific immune response in the intestine. Gut-tropic T cells are characterised by the expression of the integrin heterodimer α4β7 and the chemokine receptors CCR9 and CCR10, with CCR9 being specific for the small intestine. While CCR10 has been suggested to play a role in lymphocyte homing to the large intestine, together with CCR4, it has been implicated in lymphocyte trafficking to the skin. In addition, it is thought that induction of gut homing T cells is associated with the ability of intestinal DCs to metabolise vitamin A to retinoic acid (RA). Mucosal vaccination is known to induce mucosal and systemic immune responses, while systemic vaccination has been thought to only induce systemic immune responses. However, recent publications have shown systemic vaccination to induce mucosal immune responses. This project investigates the ability of different types of human systemic DCs to modulate expression of receptors specific to mucosal and skin homing T cells in the presence of retinoids and vitamin D. Co-culture of DCs with various T cell populations in the presence of RA revealed the ability of systemic DCs to increase α4β7 expression and decrease surface expression of cutaneous lymphocyte-associated antigen (CLA), a marker for skin homing T cells. We also showed that vitamin D plays a role in modulating CCR4 and CCR10 expression. Having investigated the ability of RA to modulate homing receptor expression on T cells, we confirmed the potential of systemic DCs to metabolize retinol and retinal in vitro by molecular means and flow cytometric analysis. Finally, we examined the role of retinoic acid receptors (RARs) in regulating α4β7 and CLA expressing T cells. This is the first study that investigates the potential of different subsets of human systemic DCs to differentially induce and modulate homing properties of T cells in vitro. The findings presented in this thesis could have major implications in the development of systemic vaccines aimed at inducing mucosal immune responses