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Bifidobacterium infantis 35624 administration induces Foxp3 T regulatory cells in human peripheral blood: potential role for myeloid and plasmacytoid dendritic cells
  1. Patrycja Konieczna1,
  2. David Groeger2,
  3. Mario Ziegler1,
  4. Remo Frei1,
  5. Ruth Ferstl1,
  6. Fergus Shanahan3,
  7. Eamonn M M Quigley3,
  8. Barry Kiely2,
  9. Cezmi A Akdis1,
  10. Liam O'Mahony1
  1. 1Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Zurich, Switzerland
  2. 2Alimentary Health Ltd., Cork, Ireland
  3. 3Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
  1. Correspondence to Dr Liam O'Mahony, SIAF, Obere Strasse 22, Davos Platz 7270, Zurich Switzerland; liam.omahony{at}siaf.uzh.ch

Abstract

Background Intestinal homoeostasis is dependent on immunological tolerance to the microbiota.

Objective To (1) determine if a probiotic could induce Foxp3 T cells in humans; (2) to elucidate the molecular mechanisms, which are involved in the induction of Foxp3 T cells by human dendritic cells.

Design Cytokine secretion and Foxp3 expression were assessed in human volunteers following Bifidobacterium infantis feeding. Monocyte-derived dendritic cells (MDDCs), myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) were incubated in vitro with B infantis and autologous lymphocytes. Transcription factor expression, costimulatory molecule expression, cytokine secretion, retinoic acid and tryptophan metabolism were analysed.

Results Volunteers fed B infantis displayed a selective increase in secretion of interleukin (IL)-10 and enhanced Foxp3 expression in peripheral blood. In vitro, MDDCs, mDCs and pDCs expressed indoleamine 2,3-dioxygenase and secreted IL-10, but not IL-12p70, in response to B infantis. MDDC and mDC IL-10 secretion was Toll-like receptor (TLR)-2/6 dependent, while pDC IL-10 secretion was TLR-9 dependent. In addition, MDDCs and mDCs expressed RALDH2, which was TLR-2 and DC-SIGN dependent. B infantis-stimulated MDDCs, mDCs and pDCs induced T cell Foxp3 expression. TLR-2, DC-SIGN and retinoic acid were required for MDDC and mDC induction of Foxp3 T cells, while pDCs required indoleamine 2,3-dioxygenase.

Conclusions B infantis administration to humans selectively promotes immunoregulatory responses, suggesting that this microbe may have therapeutic utility in patients with inflammatory disease. Cross-talk between multiple pattern-recognition receptors and metabolic pathways determines the innate and subsequent T regulatory cell response to B infantis. These findings link nutrition, microbiota and the induction of tolerance within the gastrointestinal mucosa.

  • T regulatory cells
  • dendritic cells
  • mucosal tolerance
  • microbiota
  • probiotics
  • T lymphocytes
  • bifidobacteria
  • cellular immunology
  • cytokines
  • coeliac disease
  • inflammatory bowel disease
  • mucosal immunology
  • constipation
  • gastroparesis
  • intestinal transplantation
  • gastric emptying
  • irritable bowel syndrome
  • inflammation
  • histamine
  • anti-bacterial mucosal immunity
  • molecular immunology

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Footnotes

  • Authors PK and DG contributed equally and share first authorship.

  • Funding The authors are supported by Swiss National Foundation grants (project numbers 32030-132899 and 310030-127356), Christine Kühne Center for Allergy Research and Education, Science Foundation Ireland and Alimentary Health Ltd.

  • Competing interests DG and BK are employees of the university campus company Alimentary Health Ltd. LOM, FS and EQ are consultants to Alimentary Health Ltd. FS has received research grants from GSK. CA has received research support from Novartis and Stallergenes and consulted for Actellion, Aventis and Allergopharma. PK, MZ, ReF and RuF have no conflict of interest. The content of this article was neither influenced nor constrained by these facts.

  • Ethics approval Clinical research ethics committee of the Cork Teaching Hospitals, Ireland.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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