The intestinal mucosa is the largest area directly exposed to environmental antigens, the majority of which are innocuous, originating from the diet and indigenous microbiota. This immense surface hosts a complex immune system that accounts for most of the lymphocytes and antibodies in the body. Most of these lymphocytes exhibit an ?activated-yet-resting? state, inhibiting the penetration and dissemination of pathogens while controlling excessive immune responses. A key phenomenon thought to contribute to the maintenance of this gut physiological inflammation is oral tolerance (OT), defined as an inhibition of specific immune responses towards antigens previously encountered via the oral route. The current notion is that specialized antigen-presenting cells (APCs) take up luminal antigens in the intestine and migrate to the mesenteric lymph nodes (mLN) to induce peripheral regulatory T cells (pTregs), which then circulate and prevent systemic T helper cell differentiation and inflammation upon immunization with the same antigen. However, due to the lack of temporally-controlled and, more importantly, cell-specific tools, the precise mechanisms in place that ensure a tolerogenic outcome are still poorly understood. We hypothesize that tolerance is induced by a combination of APCs and a favorable milieu for pTreg generation. Using novel genetic tools, this proposal aims to define the necessary APC subsets for induction of oral tolerance. We propose to use intersectional genetics-based mouse strains that allow ablation of specific APC lineages in a temporally-controlled fashion. Using these tools we will define the APC lineage involved in oral tolerance induction, i.e. whether common dendritic cell progenitors (CDP) or monocyte-derived APCs are necessary for tolerance establishment. Our preliminary observations support the specificity of the tools proposed to address this question. Additionally, we will investigate the role of the intestinal microbiota in antigen presentation, diet-induced pTreg differentiation and oral tolerance. By combining cell-specific genetic tools and microbiota manipulation to interfere with oral antigen presentation, we expect to define the initiating events of oral tolerance, establishing mechanisms for the prevention of pathological immune responses against innocuous antigens in the intestine. By pursuing an understanding of the main components that initiate tolerance in the gut, this proposal may provide novel strategies for the prevention of allergies and systemic inflammatory processes.
| Esterházy, Daria; Loschko, Jakob; London, Mariya et al. (2016) Classical dendritic cells are required for dietary antigen-mediated induction of peripheral T(reg) cells and tolerance. Nat Immunol 17:545-55 |
| Loschko, Jakob; Schreiber, Heidi A; Rieke, Gereon J et al. (2016) Absence of MHC class II on cDCs results in microbial-dependent intestinal inflammation. J Exp Med 213:517-34 |
| Brown, Chrysothemis C; Esterhazy, Daria; Sarde, Aurelien et al. (2015) Retinoic acid is essential for Th1 cell lineage stability and prevents transition to a Th17 cell program. Immunity 42:499-511 |
| Lee, H; Ruane, D; Law, K et al. (2015) Phenotype and function of nasal dendritic cells. Mucosal Immunol 8:1083-98 |
| Esterházy, Daria; Mucida, Daniel (2014) Serum amyloid A proteins take retinol for a ride. Trends Immunol 35:505-6 |
