Functional maturation of lamina propria dendritic cells by activation of NKT cells mediates the abrogation of oral tolerance

Abstract

We previously showed that although systemic administration of a-galactosylceramide (aGalCer) or agonistic anti-CD40 induced functional maturation of dendritic cells (DC) in mesenteric lymph nodes, only the former treatment succeeded in breaking the induction of oral tolerance. In this study, we looked for the essential factor responsible for the disruption of oral tolerance. We found that lamina propria (LP)-DC was responsible for the oral OVA presentation and that Peyer's patch was not essential for the induction of oral tolerance. Therefore, we investigated the role of LP-DC. Treatment with aGalCer but not with anti-CD40 induced the full maturation of LP-DC at an early time point. This functional activation of LP-DC was mediated by strong activation of NKT cells that reside abundantly in the small intestinal lamina propria (SI-LP) and interferon-c partially contributed to the LP-DC activation. LP-DC isolated from aGalCer-treated OVA-fed mice induced the differentiation of naïve CD4 1 T cells into Th1 and Th2 and was associated with the reduced Foxp3 1 population. In contrast, LP-DC isolated from anti-CD40-treated OVA-fed mice failed to generate Th cell differentiation but induced more Foxp3 1 CD4 1 T cells. Our results demonstrate that triggered by NKT cells in SI-LP, functional maturation of Ag-capturing DC from SI-LP is necessary for the abrogation of oral tolerance induction.

Invariant Natural Killer T Cells Contribute to the Allergic Response in Cow’s Milk Protein-Sensitized Mice

“…Since the iNKT population is affected during sensitization, this may imply that these cells contribute to the development of allergic disease or are involved in the suppression of (food) allergic disorders. iNKT cells have been shown to induce or break oral tolerance [27,33] and may suppress or enhance allergic disease in mice [18,35]. These dual mechanisms may partly be explained by the existence of different subsets of iNKT.…”

“…However, the contribution of iNKT cells, using αGalCer, in the onset of allergy is, to our knowledge, only studied in allergic asthma models [26,27,28]. With regard to food allergy, and in particular CMA, so far no data are available on the role of iNKT cells in the induction or maintenance of allergy to food ingredients and/or tolerance.…”

The interaction between invariant Natural Killer T cells and the mucosal microbiota

“…28 In contrast, the lamina propria lymphocytes, which are scattered throughout the lamina propria underneath the epithelial layer, are more diverse in their cellular composition and resemble more those of other lymphatic organs. 29 iNKT cells can be detected in the mouse intestine at frequencies only slightly lower than in other peripheral organs, like the spleen and lymph nodes (stomach, 30 small intestine, [31][32][33] large intestine [33][34][35][36][37] ). Approximately 65% (BALB/c mice) to 85% (C57BL/6 mice) of intestinal iNKT cells are NKT1 cells, with the rest largely being NKT2 cells, and no differences in this distribution were noted for IELs versus lamina propria lymphocytes.…”

Harnessing the antibacterial and immunological properties of mucosal-associated invariant T cells in the development of novel oral vaccines against enteric infections

“…This sparked interest in the application of a-Galcer as a mucosal adjuvant [33,34]. Oral administration of a-Galcer increases migration of lamina propriadendritic cells (LP-DCs) to mesenteric lymph nodes, which is suggestive of increased CCR7 expression by LP-DCs [35]. Furthermore, LP-DC activation can be enhanced through cytokine production by activated iNKT cells [36].…”

“…More recently Lee et al [46] characterized circulating MAIT cells in a large sample of 133 healthy adults and reported high variability in circulating MAIT cell numbers across subjects (0.19-21.7%). Although no significant differences in numbers between males and females were found there was a significant decrease in MAIT cell numbers in elderly subjects (n = 45, ages 61-92) versus young subjects (n = 44, ages [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40].…”