SPECIALIZED FUNCTIONS OF LAMINA PROPRIA ANTIGEN-PRESENTING CELLS IN THE MAINTENANCE OF INTESTINAL IMMUNE-HOMEOSTASIS

The intestinal immune system is daily threatened by the exposure to potentially harmful agents, such as food antigens and the gut flora. They represent, indeed, a potent immunogenic stimulus that the immune system has to tolerate. In the Gut-Associated Lymphoid Tissue, the cooperation and mutual interaction of specific environmental factors and peculiar populations of antigen-presenting cells renders the gut a suitable site for the maintenance of a tolerogenic milieu, where immunosuppressive mechanisms keep at bay unwanted deleterious immune responses. The establishment of tolerance to food antigens mostly relies on the ability of specific subsets of mononuclear cells to take up antigens in the SI (Small Intestine) and to subsequently shape the immune response, which is initiated in the draining mesenteric lymph nodes. Here, we describe a subset of resident intestinal macrophages, expressing CX3CR1, which are committed to antigen uptake. Furthermore, we show that in the absence of functional CX3CR1 receptor, which impairs the ability of these cells to sample the intestinal lumen, decreased antigen uptake and failure in the establishment of oral tolerance is observed in CX3CR1-deficient mice. As CX3CR1+ cells are sessile and poorly able to prime T cells, we hypothesized the possibility of gap junction-mediated antigenic material transfer to CD103+ dendritic cells, which have been accounted for migratory tolerogenic cells. We show, indeed, that mononuclear cells from the SI can exchange peptides and gap-junction diffusible dyes. Furthermore, CX3CR1+ macrophages and CD103+ dendritic cells express a peculiar panel of connexins, among which connexin 43 is the most expressed. We then generated mice lacking connexin 43 in CD11c+ cells. These mice displayed no change in the frequency and activation state of the different populations of lamina propria cells but decreased the levels of peripheral T regulatory cells at steady-state. In addition, we observed impaired establishment of oral tolerance to ovalbumin. This indicates that DC-expression of Cx43 is required for the establishment of oral tolerance. Whether this is due to a lessening in antigen transfer which impinges on the ability of CD103+ dendritic cells to prime T cells towards a tolerogenic phenotype or to other Cx43-dependent functions of SI mononuclear cells are still open questions, which need to be addressed.