Human gut dendritic cells drive aberrant gut-specific t-cell responses in ulcerative colitis, characterized by increased IL-4 production and loss of IL-22 and IFNγ.
: The pathogenesis of inflammatory bowel disease is incompletely understood but results from a dysregulated intestinal immune response to the luminal microbiota. CD4 T cells mediate tissue injury in the inflammatory bowel disease-associated immune response. Dendritic cells (DC) generate primary T-cell responses and mediate intestinal immune tolerance to prevent overt inflammation in response to the gut microbiota. However, most information regarding function of intestinal DC has come from mouse models, and information in humans is scarce. We show here that intestinal DC subsets are skewed in ulcerative colitis (UC) in humans, with a loss of CD103 lymph-node homing DC; this intestinal DC subset preferentially generates regulatory T cells in mice. We show infiltrates of DC negative for myeloid marker CD11c, with enhanced expression of Toll-like receptors for bacterial recognition. After mixed leukocyte reaction, DC from the inflamed UC colon had an enhanced ability to generate gut-specific CD4 T cells with enhanced production of interleukin-4 but a loss of interferon γ and interleukin-22 production. Conditioning intestinal DC with probiotic strain Lactobacillus casei Shirota in UC partially restored their normal function indicated by reduced Toll-like receptor 2/4 expression and restoration of their ability to imprint homing molecules on T cells and to generate interleukin-22 production by stimulated T cells. This study suggests that T-cell dysfunction in UC is driven by DC. T-cell responses can be manipulated indirectly through effects of bacterial conditioning on gut DC with implications for immunomodulatory effects of the commensal microbiota in vivo. Manipulation of DC to allow generation of DC-specific therapy may be beneficial in inflammatory bowel disease.
*Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark's Campus, Harrow, United Kingdom; †Gastrointestinal Division, Johns Hopkins University School of Medicine, Baltimore, Maryland; ‡Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Science, State Key Laboratory of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China; §Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom; ‖Department of Gastroenterology, St. Mark's Hospital, North West London Hospitals NHS Trust, Harrow, United Kingdom; ¶Yakult UK Ltd., South Ruislip, United Kingdom; and **Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
Elizabeth R
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Mann
David
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Bernardo
Siew C
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Ng
Rachael J
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Rigby
Hafid O
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Al-Hassi
Jon
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Landy
Simon T C
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Peake
Henning
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Spranger
Nicholas R
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English
Linda V
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Thomas
Andrew J
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Stagg
Stella C
SC
Knight
Ailsa L
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Hart
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry; D041981:Gastrointestinal Tract / Q000276:immunology* / Q000382:microbiology; D006801:Humans; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D007422:Intestines / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D007780:Lacticaseibacillus casei / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D019936:Probiotics / Q000494:pharmacology; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D000097043:Interleukin-22
D007371:Interferon-gamma; D015847:Interleukin-4; D007378:Interleukins; D000097043:Interleukin-22