Antigen-Presenting Human γδ T Cells Promote Intestinal CD4+T Cell Expression of IL-22 and Mucosal Release of Calprotectin.
The cytokine IL-22 plays a critical role in mucosal barrier defense, but the mechanisms that promote IL-22 expression in the human intestine remain poorly understood. As human microbe-responsive Vγ9/Vδ2 T cells are abundant in the gut and recognize microbiota-associated metabolites, we assessed their potential to induce IL-22 expression by intestinal CD4+T cells. Vγ9/Vδ2 T cells with characteristics of APCs were generated from human blood and intestinal organ cultures, then cocultured with naive and memory CD4+T cells obtained from human blood or the colon. The potency of blood and intestinal γδ T-APCs was compared with that of monocytes and dendritic cells, by assessing CD4+T cell phenotypes and proliferation as well as cytokine and transcription factor profiles. Vγ9/Vδ2 T cells in human blood, colon, and terminal ileum acquired APC functions upon microbial activation in the presence of microenvironmental signals including IL-15, and were capable of polarizing both blood and colonic CD4+T cells toward distinct effector fates. Unlike monocytes or dendritic cells, gut-homing γδ T-APCs employed an IL-6 independent mechanism to stimulate CD4+T cell expression of IL-22 without upregulating IL-17. In human intestinal organ cultures, microbial activation of Vγ9/Vδ2 T cells promoted mucosal secretion of IL-22 and ICOSL/TNF-α-dependent release of the IL-22 inducible antimicrobial protein calprotectin without modulating IL-17 expression. In conclusion, human γδ T-APCs stimulate CD4+T cell responses distinct from those induced by myeloid APCs to promote local barrier defense via mucosal release of IL-22 and calprotectin. Targeting of γδ T-APC functions may lead to the development of novel gut-directed immunotherapies and vaccines.
Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
Christopher J
CJ
Tyler
Centre for Immunobiology, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom.
Neil E
0000-0002-4330-4747
NE
McCarthy
Centre for Immunobiology, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom.|Department of Gastroenterology, The Royal London Hospital, Barts Health NHS Trust, London E1 1BB, United Kingdom; and.
James O
JO
Lindsay
Centre for Immunobiology, The Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom; eberlm@cf.ac.uk a.stagg@qmul.ac.uk.
Andrew J
AJ
Stagg
Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.|Systems Immunity Research Institute, Cardiff University, Cardiff CF14 4XN, United Kingdom.
Bernhard
0000-0002-4354-4572
B
Moser
Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom; eberlm@cf.ac.uk a.stagg@qmul.ac.uk.|Systems Immunity Research Institute, Cardiff University, Cardiff CF14 4XN, United Kingdom.
Matthias
0000-0002-9390-5348
M
Eberl
D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003106:Colon / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods*; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000378:metabolism; D019409:Interleukin-15 / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology*; D039841:Leukocyte L1 Antigen Complex / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097043:Interleukin-22
D060945:Inducible T-Cell Co-Stimulator Ligand; D019409:Interleukin-15; D015850:Interleukin-6; D007378:Interleukins; D039841:Leukocyte L1 Antigen Complex; D008070:Lipopolysaccharides; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22; C498514:ICOSLG protein, human