Antigen-Presenting Human γδ T Cells Promote Intestinal CD4+ T Cell Expression of IL-22 and Mucosal Release of Calprotectin

• Published in: The Journal of immunology (1950) Vol. 198; no. 9; pp. 3417 - 3425
• Main Authors: Tyler, Christopher J, McCarthy, Neil E, Lindsay, James O, Stagg, Andrew J, Moser, Bernhard, Eberl, Matthias
• Format: Journal Article
• Language: English
• Published: England American Association of Immunologists 01.05.2017; AAI
• Subjects: Antigen Presentation; Antigen-presenting cells; Blood; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Cell activation; Cell proliferation; Cells, Cultured; Clinical and Human Immunology; Coculture Techniques; Colon; Colon - immunology; Cytokines; Dendritic cells; Digestive system; Effector cells; Gastrointestinal tract; Humans; Ileum; Immunologic Memory; Immunological memory; Immunotherapy; Immunotherapy - methods; Inducible T-Cell Co-Stimulator Ligand - metabolism; Interleukin 15; Interleukin 17; Interleukin 22; Interleukin 6; Interleukin-15 - immunology; Interleukin-6 - metabolism; Interleukins - genetics; Interleukins - metabolism; Intestinal Mucosa - immunology; Intestine; Leukocyte L1 Antigen Complex - metabolism; Lipopolysaccharides - immunology; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Memory cells; Metabolites; Monocytes; Mucosa; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Tumor necrosis factor; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1700003

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.