Phenotype and function of intestinal CD103+ dendritic cells

Sammanfattning: Mucosal tissues such as the intestine present an enormous surface area to the outside environment and are continually exposed to foreign antigens in food and microflora. Thus, the intestinal mucosa must must remain tolerant to these innocuous antigens while at same time be able to mount effective immune responses to pathogens. Intestinal dendritic cells (DCs) and macrophages, found throughout the villous lamina propria and intestinal lymphoid tissue in both mice and humans are thought to play key roles in this process. DCs at these sites constantly sample and process both luminal and self-antigens and are key players in presenting these antigens to T cells. Recently, intestinal CD103+ DCs have been shown to promote induction of both gut homing receptors on responding T cells and differentiation of FoxP3+ regulatory T cells via the vitamin A metabolite retinoic acid (RA). Another intestinal DC/macrophage subset, expressing the chemokine receptor CX3CR1+ has been suggested to take up intestinal luminal antigens via transepithelial dendrites. The focus of this thesis has been to phenotypically and functionally characterize intestinal CD103+ DCs and to investigate the mechanisms that underlie their enhanced ability to generate gut homing T cells. In this thesis we demonstrate that CD103+ DCs present in the murine small intestinal mucosa and draining mesenteric lymph nodes (MLN) have an enhanced ability to deliver RA signals and induce gut homing receptors on responding T cells in vitro compared to CD103- DCs and CD103+ DCs outside the intestine. Importantly we show that that CD103+ DCs also are present in human MLN and have a similar ability to induce RA dependent gut tropism on T cells. We demonstrate that CD103+ DCs and CX3CR1+ cells are non- overlapping populations of intestinal cells that differ both in phenotype and in function. Our results suggest that CD103+ DCs are the major migratory DC population in the intestinal mucosa and play a central role in initiating immune responses to luminal antigen in draining MLNs. In contrast we find that CX3CR1+ cells resemble tissue macrophages, are non-migratory and inefficient at activating naïve T cells. We further show that both populations have different growth factor requirements and turnover rates in the intestinal mucosa. We have also examined potential mechanisms underlying the selective ability of intestinal CD103+ DCs to metabolize vitamin A. Results from these studies suggest that the Vitamin A metabolite RA itself induces retinol-metabolizing activity in CD103+ DCs in vivo, and that bile is an important source of these retinoids. Collectively, these studies have contributed to our knowledge of the mechanisms regulating intestinal immune responses and will hopefully lead to novel strategies for treatments for intestinal inflammatory diseases and mucosal vaccine design.