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

By T. Worbs, U. Bode, Sheng Yan, M. Hoffmann, G. Hintzen, G. Bernhardt, R. Förster, O. Pabst. Journal of Experimental Medicine, 2006

722 citations recorded by the source corpus.

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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/9e49a9014999e0be9b06464b2b1fbe3a0c375e5b

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In Immunology

1. Y. Belkaid
2. O. Harrison
3. Caroline L. Sokol
4. Werner Müller
5. F. Quintana
6. R. Förster
7. J. Coombes
8. F. Powrie

Citations in the corpus

• Homeostatic immunity and the microbiota (2017, positive): “…available in PMC 2018 April 18. throughout the lifespan of the host and disruption of the homeostasis of these cells in the GI tract results in loss of oral tolerance and development of aberrant effector responses in the gut (Josefowicz et al., 2012b; Mucida et al., 2005; Worbs et al., 2006).”
• The chemokine system in innate immunity. (2015, background): “CCR7 signaling is a common pathway for homeostatic DC migration from diverse peripheral tissues; CCR7 has been shown to be essential for migration of DCs from the skin, lung, and gastrointestinal tract (Ohl et al. 2004; Worbs et al. 2006).”
• Oral tolerance (2011, background): “Orally administered antigens are primarily recognized by DCs in the MLN, which require afferent lymph to process oral antigen and induction of oral tolerance is impeded by mesenteric lymphadenectomy (37).”
• Role of the Microbiota in Immunity and inflammation (2014, background): “…maintain both peripheral and mucosal homeostasis throughout the lifespan of the host, and disruption of the homeostasis of these cells results in loss of oral tolerance and development of aberrant effector responses in the gut (Josefowicz et al., 2012a; Mucida et al., 2005; Worbs et al., 2006).”
• Dendritic cells in intestinal immune regulation (2008, positive): “The importance of this constitutive carriage of antigen to the MLNs is suggested by studies in which impaired trafficking of DCs, as occurs in Ccr7 −/− mice, results in defective induction of tolerance to oral antigen”
• Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions (2009, background): “10 cells i.v. 3 d after intralymphatic injection, T cell proliferation was determined in MLN and peripheral LNs. Injection of CD103+ DC induced proliferation of antigen-specific DO11.”
• Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. (2011, methodology): “Presentation of regular food protein largely depends on antigen presentation by classic dendritic cells (DCs) in the gutdraining mesenteric lymph nodes (mLN) (Worbs et al., 2006).”
• Chemokines and chemokine receptors: positioning cells for host defense and immunity. (2014, background): “Similarly, gastrointestinal and lungresident DCs spontaneously migrate into mesenteric and mediastinal LNs, respectively, via a CCR7-dependent process, underscoring the role of CCR7 in homeostatic migration of peripheral DCs (50).”