Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells

Abstract

Oral tolerance induction is a key feature of intestinal immunity, generating systemic nonresponsiveness to ingested antigens. In this study, we report that orally applied soluble antigens are exclusively recognized in the intestinal immune system, particularly in the mesenteric lymph nodes. Consequently, the initiation of oral tolerance is impeded by mesenteric lymphadenectomy. Small bowel transplantation reveals that mesenteric lymph nodes require afferent lymph to accomplish the recognition of orally applied antigens. Finally, oral tolerance cannot be induced in CCR7-deficient mice that display impaired migration of dendritic cells from the intestine to the mesenteric lymph nodes, suggesting that immunologically relevant antigen is transported in a cell-bound fashion. These results demonstrate that antigen transport via afferent lymphatics into the draining mesenteric lymph nodes is obligatory for oral tolerance induction, inspiring new therapeutic strategies to exploit oral tolerance induction for the prevention and treatment of autoimmune diseases.

MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103+ Dendritic Cells Independently of TNF-α and the Gut Microbiota

“…This has allowed us to perform short-term in vivo BrdU pulse-chase experiments to assess the mechanisms regulating entry of CD103 + DCs into the MLN. In agreement with a critical role for CCR7 in this process (9,13,39), we show that the accumulation of BrdU-labeled CD103 + DCs in the MLN is essentially shut off in CCR7 2/2 mice. Further to this, our BrdU pulse-chase experiments show that MHC-II high DCs accumulate with a delayed kinetics in the MLN as compared with their MHC-II low counterparts, which is consistent with the MHC-II high phenotype of all DCs in mesenteric lymph (15,40).…”

“…These DCs display an enhanced ability to induce the gut-homing molecules CCR9 and a 4 b 7 on T cells and, in the presence of TGF-b, support the differentiation of Foxp3 + T regulatory (Treg) cells in vitro through mechanisms involving the vitamin A metabolite retinoic acid (RA) (9,11,12). The large majority of MLN CD103 + DCs appears to represent small intestinal (SI) lamina propria (LP)-derived migratory DCs as they are selectively reduced in MLN, but not in the SI LP, of CCR7-deficient mice (9,13) and in BrdU pulse-chase experiments accumulate with delayed kinetics in the MLN compared with the SI LP (14). Consistent with this, the majority of DCs in thoracic duct lymph collected from mice after mesenteric lymphadenectomy express CD103 (15).…”

“…In the gut this process seems to be intimately linked to intestinal homeostasis, as induction of oral tolerance to ingested proteins is defective after surgical removal of the MLN as well as in CCR7-deficient animals (13), and in vivo expansion of DC numbers by FMS-like tyrosine kinase 3 ligand augments oral tolerance (19). In the current study, we assessed the mechanism underlying the steady-state migration of CD103 + DCs from the SI LP to the MLN.…”

Anatomic location defines antigen presentation by dendritic cells to T cells in response to intravenous soluble antigens

“…Anatomic location, then, seems to determine the ability of each DC subset to provide signal 1 to T cells. Based on the capacity of DC subsets to trigger Ag-specific T cell division, we summarized our findings in Table 1. MLN DC presumably show the characteristics of intestinal DC, since intestinal DC are known to home to the MLN in steady state in a CCR7-dependent manner and compose a major population of DC in this lymphoid tissue [22,23]. Recent studies described unique functional characteristics of intestinal DC, such as imprinting T cells and B cells to home to the intestine [24,25] and their responsiveness against Toll-like receptor ligands [26].…”

Lamina propria dendritic cells: For whom the bell TOLLs?

“…They could be involved in bacterial killing without inducing inflammation [19], control the function of DC [9] or they might migrate to MLN for tolerance induction, but it should be evaluated whether they have access to the T cell area. It is unlikely that macrophages might induce tolerance in the LP, as MLN have been shown to be the site for oral tolerance induction and migration of CCR7 + cells to MLN is also required [20]. In conclusion, more immunohistochemical and functional studies are needed to further elucidate the function of gut antigen presenting cells, a very exciting field of research.…”