Peyer's patches are required for oral tolerance to proteins

Abstract

To clarify the role of Peyer's patches in oral tolerance induction, BALB͞c mice were treated in utero with lymphotoxin ␤-receptor Ig fusion protein to generate mice lacking Peyer's patches. When these Peyer's patch-null mice were fed 25 mg of ovalbumin (OVA) before systemic immunization, OVA-specific IgG Ab responses in serum and spleen were seen, in marked contrast to low responses in OVA-fed normal mice. Further, high T-cell-proliferative-and delayed-type hypersensitivity responses were seen in Peyer's patch-null mice given oral OVA before systemic challenge. Higher levels of CD4 ؉ T-cell-derived IFN-␥, IL-4, IL-5, and IL-10 syntheses were noted in Peyer's patch-null mice fed OVA, whereas OVA-fed normal mice had suppressed cytokine levels. In contrast, oral administration of trinitrobenzene sulfonic acid (TNBS) to Peyer's patch-null mice resulted in reduced TNBS-specific serum Abs and splenic B cell antitrinitrophenyl Ab-forming cell responses after skin painting with picryl chloride. Further, when delayed-type hypersensitivity and splenic T cell proliferative responses were examined, Peyer's patch-null mice fed TNBS were unresponsive to hapten. Peyer's patch-null mice fed trinitrophenyl-OVA failed to induce systemic unresponsiveness to hapten or protein. These findings show that organized Peyer's patches are required for oral tolerance to proteins, whereas haptens elicit systemic unresponsiveness via the intestinal epithelial cell barrier.

Functional CD25– and CD25+ mucosal regulatory T cells are induced in gut‐draining lymphoid tissue within 48 h after oral antigen application

“…A comparison of the onset of T cell activation in the gutdraining lymphoid tissues with the onset in peripheral non-draining tissues further emphasizes the significance of these tissues in the induction and differentiation of mucosal Tr cells. The active involvement of the draining lymphoid organs confirms earlier reports on the dependency of intact PP and MLN in oral tolerance induction [18,19]. The multiple divisions of the antigen-specific T cells in these locations found within 24-48 h demonstrate that an extremely efficient antigen uptake and presentation process has occurred by this time, most likely by DC residing in the gut epithelium [32].…”

“…We hypothesize that specific conditions in the gut-draining lymphoid tissues are essential for Tr cell induction, as inferred by the finding that oral tolerance is aborted in the absence of mesenteric lymph nodes (MLN) [17], emphasizing the importance of this draining route. Whether the Peyer's patches (PP) are also directly involved in the process is debatable [18][19][20]. That an active response to oral ovalbumin (OVA) occurs in the PP and MLN is revealed by the detection of activated T cells within the first days post-OVA treatment, based on CD69 expression and an increase in T cell number [21].…”

Inhalation Tolerance Is Induced Selectively in Thoracic Lymph Nodes but Executed Pervasively at Distant Mucosal and Nonmucosal Tissues

“…route, the nose-draining cervical LNs appeared to be the predominant site for tolerance induction (48,49). In models of orally fed Ag, both mesenteric LNs and Peyer's patches were shown to be the predominant sites of Ag presentation (58 -61), and critical for the induction of oral tolerance (59,62). To a lesser extent, oral Ag delivery has also been shown to induce clonal expansion of Ag-specific T cells in the spleen and, in cases in which high doses of Ag are administered, even in peripheral LNs (61,63,64).…”

Antigen‐induced, tolerogenic CD11c+,CD11b+ dendritic cells are abundant in Peyer's patches during the induction of oral tolerance to type II collagen and suppress experimental collagen‐induced arthritis

“…Many reports have suggested that Peyer's patches, which are lymphoid nodules interspersed among the intestinal villi, are essential for mucosal immune responses and oral tolerance to soluble antigens (2,3,10,11). Peyer's patches contain professional antigen-presenting cells (APCs) known as dendritic cells (DCs), which are known to play an important role in both immune responses and immune tolerance in the intestinal mucosa.…”