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

Christopher J Tyler,Neil E Mccarthy,James O Lindsay,Andrew J Stagg,Matthias Eberl,Bernhard Moser

doi:10.4049/jimmunol.1700003

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 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.

Highlights

We demonstrate that human microbe–responsive Vg9/Vd2 T cells readily acquire gut-homing and Ag-presenting functions, and stimulate CD4+ T cell responses distinct from those induced by monocytes or dendritic cell (DC)
This study demonstrates that microbial activation of human Vg9/Vd2 T cells in the peripheral blood, colon, and ileum stimulates these cells to act as professional APCs that can efficiently polarize CD4+ T cells toward specific effector fates distinct from those induced by monocytes or DCs
Acquisition of gd T-APC function was potently induced by microbial activation in the presence of the epithelial-derived cytokine IL-15, suggesting a role in local barrier defense via induction of IL-22 and calprotectin release, whereas symbiosis-regulating Th17 responses may instead be mediated by myeloid APCs

Summary

Introduction

We demonstrate that human microbe–responsive Vg9/Vd2 T cells readily acquire gut-homing and Ag-presenting functions, and stimulate CD4+ T cell responses distinct from those induced by monocytes or DCs. Unlike myeloid APCs, blood and intestinal gd T-APCs failed to promote IL-17 but were capable of potent IL-22 induction in naive and memory CD4+ T cells via a costimulatory pathway that required inducible T-cell costimulator ligand (ICOSL) and TNF-a but not IL-6. Colonic Vg9/Vd2 T cells from HMB-PP–stimulated gut tissue displayed an increased ability to induce proliferation and differentiation of naive CD4+ T cells toward expression of IFN-g and IL-22, compared with unstimulated controls (Fig. 1A), whereas only trace numbers of IL-17+ CD4+ T cells were generated in these cocultures.

Results

Conclusion