Mesenteric lymph nodes at the center of immune anatomy

Abstract

The surface of the intestinal mucosa is constantly assaulted by food antigens and enormous numbers of commensal microbes and their products, which are sampled by dendritic cells (DCs). Recent work shows that the mesenteric lymph nodes (MLNs) are the key site for tolerance induction to food proteins and that they also act as a firewall to prevent live commensal intestinal bacteria from penetrating the systemic immune system.

Figure 1.

Induction of oral tolerance. To induce oral tolerance animals are fed with soluble protein (such as ovalbumin; OVA). Tolerance can be induced with single high doses, typically 100 mg, or several repeated low doses, typically 1–25 mg. Control animals are fed PBS. 2 weeks after feeding animals are injected subcutaneously with protein in adjuvant (such as OVA with complete Freund's adjuvant; CFA). 2–3 weeks after subcutaneous priming, animals are challenged with heat- aggregated protein in the ear or footpad. Changes in footpad or ear thickness are then recorded, usually 24 or 48 h after challenge (delayed type hypersensitivity; DTH). Tolerized animals exhibit reduced DTH reactions. Antibody responses are assessed after serum collection, and in vitro techniques, such as antigen-stimulated thymidine incorporation, are used to assess T cell responses. Using these readouts both B and T cell responses are attenuated in tolerized animals.

Figure 2.

Functional anatomy of induction of immune responses by intestinal antigens. Abundant protein antigens and live commensal bacteria are present in the intestine. Antigenic peptides can pass into the bloodstream through one of the tributaries of the hepatic portal vein or are taken up by DCs in the subepithelial region of the Peyer's patches and carried to the MLNs via the afferent lymphatics. Although it is possible for circulating peptides to tolerize T cells in the liver or peripheral lymph nodes, presentation in the MLNs is the dominant tolerogenic pathway. Commensal bacteria are also sampled by intestinal DCs and induce IgA responses in the Peyer's patches; although very small numbers of commensals can be carried to MLN by DC, systemic tolerance to these organisms is not induced. Because the commensal laden DCs do not penetrate further than the MLN, the systemic immune system is protected from unwanted priming reactions from live bacteria.