Antigen-presenting human γδ T-cells promote intestinal CD4+ T-cell expression of IL-22 and mucosal release of calprotectin

Tyler, Christopher J., McCarthy, Neil E., Lindsay, James O., Stagg, Andrew J., Moser, Bernhard ORCID: https://orcid.org/0000-0002-4354-4572 and Eberl, Matthias ORCID: https://orcid.org/0000-0002-9390-5348 2017. Antigen-presenting human γδ T-cells promote intestinal CD4+ T-cell expression of IL-22 and mucosal release of calprotectin. The Journal of Immunology 198 (9) , 1700003. 10.4049/jimmunol.1700003

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Abstract

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 Vg9/Vd2 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. Vg9/Vd2 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 gd 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. Vg9/Vd2 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 gd 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 Vg9/Vd2 T cells promoted mucosal secretion of IL-22 and ICOSL/TNF-a–dependent release of the IL-22 inducible antimicrobial protein calprotectin without modulating IL-17 expression. In conclusion, human gd 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 gd T-APC functions may lead to the development of novel gut-directed immunotherapies and vaccines.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Funders:	MRC
Date of First Compliant Deposit:	30 March 2017
Date of Acceptance:	17 February 2017
Last Modified:	04 May 2023 23:37
URI:	https://orca.cardiff.ac.uk/id/eprint/99535

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