Goblet cell associated antigen passages support the induction and maintenance of oral tolerance


Tolerance to innocuous antigens from the diet and the commensal microbiota is a fundamental process essential to health. Why tolerance is efficiently induced to substances arising from the hostile environment of the gut lumen is incompletely understood but may be related to how these antigens are encountered by the immune system. We observed that goblet cell associated antigen passages (GAPs), but not other pathways of luminal antigen capture, correlated with the acquisition of luminal substances by lamina propria (LP) antigen presenting cells (APCs) and with the sites of tolerance induction to luminal antigens. Strikingly this role extended beyond antigen delivery. The GAP function of goblet cells facilitated maintenance of pre-existing LP T regulatory cells (Tregs), imprinting LP-dendritic cells with tolerogenic properties, and facilitating LP macrophages to produce the immunomodulatory cytokine IL-10. Moreover, tolerance to dietary antigen was impaired in the absence of GAPs. Thus, by delivering luminal antigens, maintaining pre-existing LP Tregs, and imprinting tolerogenic properties on LP-APCs GAPs support tolerance to substances encountered in the hostile environment of the gut lumen.

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Fig. 1: Goblet cell associated antigen passages (GAPs) are present at the sites where tolerance to luminal substances is induced in the steady state.
Fig. 2: Goblet cells support antigen presenting cell acquisition of luminal antigen and CD4+ T cell responses to luminal antigen in the gut draining lymph nodes.
Fig. 3: The GAP function of goblet cells supports the acquisition of, and CD4+ T cell responses to, luminal antigen.
Fig. 4: GAPs support the maintenance and induction of pTregs.
Fig. 5: GAPs support the imprinting of LP-APCs.
Fig. 6: GAPs support tolerance to dietary antigen in the SI and tolerance to luminal antigens in the distal colon.


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Supported by grants: DK097317, AI131342, AI112626, DK109006, AI136515, AI 140755, and Crohn’s and Colitis Foundation Research Fellowship Award 348359 and Swedish Research Council International Postdoc Award 2014-00366. The authors wish to thank Mark J Miller for advice and assistance with in vivo two-photon imaging. The Washington University Digestive Diseases Research Center Core, supported by NIH grant P30 DK052574 assisted with imaging. Two photon in vivo imaging was performed at the Washington University School of Medicine In Vivo Imaging Core. The High Speed Cell Sorter Core at the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO. provided flow-cytometric cell sorting services. The Siteman Cancer Center is supported in part by NCI Cancer Center Support Grant P30 CA91842.

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D.H.K., J.K.G., K.A.K., K.G.M., A.N.F., S.S.B., and J.E.D. performed the experiments. D.H.K., J.K.G., K.G.M., S.P.H., C.S.H., and R.D.N. designed the study. D.H.K., J.K.G., S.P.H., C.S.H., and R.D.N. wrote the manuscript. All authors have reviewed and agree with the manuscript content.

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Correspondence to Rodney D. Newberry.

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R.D.N., K.A.K., and K.G.M. are inventors on U.S. Nonprovisional Application Serial No. 15/880,658 Compositions And Methods For Modulation Of Dietary And Microbial Exposure.

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Kulkarni, D.H., Gustafsson, J.K., Knoop, K.A. et al. Goblet cell associated antigen passages support the induction and maintenance of oral tolerance. Mucosal Immunol 13, 271–282 (2020). https://doi.org/10.1038/s41385-019-0240-7

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