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. 2006 Mar 20;203(3):519-27.
doi: 10.1084/jem.20052016. Epub 2006 Mar 13.

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

Tim Worbs  1 , Ulrike Bode, Sheng Yan, Matthias W Hoffmann, Gabriele Hintzen, Günter Bernhardt, Reinhold Förster, Oliver Pabst
Affiliations

VSports最新版本 - Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells

Tim Worbs et al. J Exp Med. .

Abstract

Oral tolerance induction is a key feature of intestinal immunity, generating systemic nonresponsiveness to ingested antigens VSports手机版. 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. .

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Figures

Figure 1.
Figure 1.
Oral administration of antigen does not induce proliferation of antigen-specific T cells in pLN and spleen in the presence of FTY720. 1 d after adoptive transfer of CFSE-labeled DO11.10 cells, wild-type recipients were fed 100 mg ovalbumin in PBS or PBS alone. Subsequently, mice were either treated with FTY720 (starting 16 h after antigen feeding) or mock treated. 2, 4, and 8 d after feeding of ovalbumin, mice were killed and proliferation of ovalbumin-specific T cells was analyzed. Dot plots are gated on CD4-positve lymphocytes.
Figure 2.
Figure 2.
Recirculation of lymphocytes is dispensable for oral tolerance induction. Wild-type mice were fed four doses of 25 mg ovalbumin in PBS (black bars) or PBS alone (white bars) under continuous treatment with FTY720 (+FTY720) or mock treatment (−FTY720). Subsequently, on day 28, mice were immunized by subcutaneous injection of ovalbumin in PBS/CFA emulsion and challenged on day 41 (see Materials and methods). Tolerance induction was analyzed by measurement of DTH reactions 48 h after challenge. The experimental procedure is depicted in the flow chart. #, control of peripheral blood cell counts to monitor FTY720-induced lymphopenia. Data shown have been obtained for 11 or 12 mice in each group. Error bars represent SEM.
Figure 3.
Figure 3.
Tolerogenic potential is largely confined to MLN. Wild-type mice were fed two doses of 25 mg ovalbumin under continuous FTY720 treatment and subsequently underwent surgical removal of MLN. Color images demonstrate absence of MLN in mice that underwent mesenteric lymphadenectomy (−MLN) compared with unmanipulated controls (+MLN). Arrows indicate (original) position of MLN. The experimental procedure is depicted in the flow chart. #, control of peripheral blood cell counts to monitor FTY720-induced lymphopenia. Data shown have been obtained with 10 mice that underwent mesenteric lymphadenectomy and four mice in each of the unmanipulated control groups. Error bars represent SEM.
Figure 4.
Figure 4.
Oral administration of antigen does not induce proliferation of antigen-specific T cells in transplanted PP and MLN that are connected to the host circulation but not to afferent lymphatics of the host intestine. Intestinal segments together with completely intact donor MLN were transplanted into syngenic wild-type recipients. Grafts were connected to the host blood circulation and both graft ends were exteriorized as stomata. Subsequently, recipient mice were adoptively transferred with 107 CFSE-labeled OTII cells. 2 d after feeding of 100 mg ovalbumin (oral), proliferation of ovalbumin-specific TCR-transgenic T cells occurred only in endogenous but not in transplanted organs, whereas systemic administration of antigen by intravenous injection (i.v.) resulted in comparable reactions in grafted and host gut-associated lymphoid tissue. Note that naive transgenic cells were present in the grafted MLN/PP, indicating a successful coupling to the recipients' lymphocyte recirculation. Dot plots are gated on Vα2/Vβ5-positive lymphocytes.
Figure 5.
Figure 5.
Mesenteric lymphadenectomy does not result in antigen recognition in peripheral lymphoid organs after oral administration of antigen. 5 wk after mesenteric lymphadenectomy, MLN-explanted mice (−MLN) and unmanipulated wild-type controls (+MLN) were adoptively transferred with 107 CFSE-labeled DO11.10 cells. Oral administration of 100 mg ovalbumin 1 d later did not result in proliferation of ovalbumin-specific TCR-transgenic T cells in pLN and spleen 2 d after feeding, irrespective of the presence of the MLN. Dot plots are gated on DO11.10 TCR-positive lymphocytes.
Figure 6.
Figure 6.
(A) Induction of T cell proliferation in MLN upon antigen feeding depends on CCR7. Wild-type, plt/plt, and CCR7-deficient mice were adoptively transferred with 107 CFSE-labeled OTII cells and fed 100 mg ovalbumin 1 d later. Proliferation of ovalbumin-specific T cells in MLN was analyzed 2 d after antigen administration. Dot plots are gated on Vα2/Vβ5-positive lymphocytes. In contrast with wild-type mice, no induction of T cell proliferation occurred in MLN of plt/plt mutants and CCR7-deficient animals. (B) Analysis of DCs in LP and MLN. DCs in the LP and MLN of wild-type (white bars) and CCR7-deficient mice (black bars) were analyzed by flow cytometry and immunofluorescent microscopy. No significant differences in the number and phenotype of DCs were observed in the LP, whereas MLN of CCR7 mutants harbored severely decreased numbers of DCs compared with wild-type mice. (C) Oral tolerance induction is impaired in CCR7-deficient mice. Wild-type and CCR7-deficient mice were fed 25 mg ovalbumin (black bars) on days 0 and 2 or mock treated (white bars). Subsequently, on day 9, mice were immunized by intraperitoneal injection of ovalbumin in PBS/CFA emulsion and challenged on day 22 (see Materials and methods). Tolerance induction was analyzed by measurement of DTH reactions 48 h after challenge. Data shown have been obtained with the following: n = 7 wild-type mice (PBS); n = 9 wild-type mice (Ova); n = 11 CCR7−/− mice (PBS); n = 12 CCR7−/− mice (Ova). Error bars represent SD in B and SEM in C.
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References

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