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Dendritic cells (DCs) in mesenteric lymph nodes (MLNs) induce Foxp3 regulatory T cells to regulate immune responses to beneficial or non-harmful agents in the intestine, such as commensal bacteria and foods. Several studies in MLN DCs have revealed that the CD103 DC subset highly induces regulatory T cells, and another study has reported that MLN DCs from programmed death ligand 1 (PD-L1) -deficient mice could not induce regulatory T cells. Hence, the present study investigated the expression of these molecules on MLN CD11c cells. Four distinct subsets expressing CD103 and/or PD-L1 were identified, namely CD11b CD103 PD-L1 , CD11b CD103 PD-L1 , CD11b CD103 PD-L1 and CD11b CD103 PD-L1 . Among them, the CD11b CD103 PD-L1 DC subset highly induced Foxp3 T cells. This subset expressed Aldh1a2 and Itgb8 genes, which are involved in retinoic acid metabolism and transforming growth factor-β (TGF-β) activation, respectively. Exogenous TGF-β supplementation equalized the level of Foxp3 T-cell induction by the four subsets whereas retinoic acid did not, which suggests that high ability to activate TGF-β is determinant for the high Foxp3 T-cell induction by CD11b CD103 PD-L1 DC subset. Finally, this subset exhibited a migratory DC phenotype and could take up and present orally administered antigens. Collectively, the MLN CD11b CD103 PD-L1 DC subset probably takes up luminal antigens in the intestine, migrates to MLNs, and highly induces regulatory T cells through TGF-β activation.

Background and ObjectiveTo improve the efficacy and safety of tolerance induction for food allergies, identifying the tissues responsible for inducing intestinal inflammation and subsequent oral tolerance is important. We used OVA23-3 mice, which express an ovalbumin-specific T-cell receptor, to elucidate the roles of local and systemic immune tissues in intestinal inflammation.Methods and ResultsOVA23-3 mice developed marked enteropathy after consuming a diet containing egg white (EW diet) for 10 days but overcame the enteropathy (despite continued moderate inflammation) after receiving EW diet for a total of 28 days. Injecting mice with anti-IL-4 antibody or cyclosporine A confirmed the involvement of Th2 cells in the development of the enteropathy. To assess the individual contributions of Peyer’s patches (PPs), mesenteric lymph nodes (MLNs), and the spleen to the generation of effector CD4+ T-cells, we analyzed the IL-4 production, proliferation in response to ovalbumin, and CD4+ T-cell numbers of these tissues. EW feeding for 10 days induced significant IL-4 production in PPs, the infiltration of numerous CD4+ T-cells into MLNs, and a decrease in CD4+ T-cell numbers in spleen. On day 28, CD4+ T-cells from all tissues had attenuated responses to ovalbumin, suggesting tolerance acquisition, although MLN CD4+ T-cells still maintained IL-4 production with proliferation. In addition, removal of MLNs but not the spleen decreased the severity of enteropathy and PP-disrupted mice showed delayed onset of EW-induced inflammatory responses. Disruption of peripheral lymphoid tissues or of both PPs and MLNs almost completely prevented the enteropathy.ConclusionsPPs and MLNs coordinately promote enteropathy by generating effector T-cells during the initial and exacerbated phases, respectively; the spleen is dispensable for enteropathy and shows tolerogenic responses throughout EW-feeding. The regulation of PPs may suppress the initiation of intestinal inflammation, subsequently restricting MLNs and inhibiting the progression of food-allergic enteropathy.

Our mouse model would be useful to investigate inflammatory and regulatory mechanisms in food-induced intestinal allergies. Our results suggest potential gastrointestinal inflammation in patients undergoing OIT as continuous administration of allergenic foods, even though the therapy may induce clinical tolerance.

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