Interferon-γ Induces Expression of MHC Class II on Intestinal Epithelial Cells and Protects Mice from Colitis

Christoph Thelemann,Remzi Onur Eren,Christoph Mueller,Anais Duval,Jennifer Brasseit,Christine Lavanchy,Vanessa Mack,Walter Reith,Hanifa Bouzourene,Hans Acha-Orbea,Muriel Rosa,Manuel Coutaz

doi:10.1371/journal.pone.0086844

Abstract

Immune responses against intestinal microbiota contribute to the pathogenesis of inflammatory bowel diseases (IBD) and involve CD4+ T cells, which are activated by major histocompatibility complex class II (MHCII) molecules on antigen-presenting cells (APCs). However, it is largely unexplored how inflammation-induced MHCII expression by intestinal epithelial cells (IEC) affects CD4+ T cell-mediated immunity or tolerance induction in vivo. Here, we investigated how epithelial MHCII expression is induced and how a deficiency in inducible epithelial MHCII expression alters susceptibility to colitis and the outcome of colon-specific immune responses. Colitis was induced in mice that lacked inducible expression of MHCII molecules on all nonhematopoietic cells, or specifically on IECs, by continuous infection with Helicobacter hepaticus and administration of interleukin (IL)-10 receptor-blocking antibodies (anti-IL10R mAb). To assess the role of interferon (IFN)-γ in inducing epithelial MHCII expression, the T cell adoptive transfer model of colitis was used. Abrogation of MHCII expression by nonhematopoietic cells or IECs induces colitis associated with increased colonic frequencies of innate immune cells and expression of proinflammatory cytokines. CD4+ T-helper type (Th)1 cells - but not group 3 innate lymphoid cells (ILCs) or Th17 cells - are elevated, resulting in an unfavourably altered ratio between CD4+ T cells and forkhead box P3 (FoxP3)+ regulatory T (Treg) cells. IFN-γ produced mainly by CD4+ T cells is required to upregulate MHCII expression by IECs. These results suggest that, in addition to its proinflammatory roles, IFN-γ exerts a critical anti-inflammatory function in the intestine which protects against colitis by inducing MHCII expression on IECs. This may explain the failure of anti-IFN-γ treatment to induce remission in IBD patients, despite the association of elevated IFN-γ and IBD.

Highlights

inflammatory bowel diseases (IBD) are chronic and recurring inflammatory disorders affecting the human gastrointestinal tract
Characterisation of T cells in pIV2/2 K14 class II transactivator (CIITA) Tg Mice It was previously shown that pIV2/2 K14 CIITA Tg mice are deficient in nonhematopoietic major histocompatibility complex class II (MHCII) expression but harbour normal thymic and peripheral CD4+ T cell populations displaying WT T cell receptor Vb-chain repertoires [18]
Since the provision of costimulation by antigenpresenting cells (APCs) is a prerequisite for immunogenic T cell activation, we examined whether intestinal epithelial cells (IEC) express costimulatory molecules in healthy and/or colitic mice

Summary

Introduction

IBDs are chronic and recurring inflammatory disorders affecting the human gastrointestinal tract. IECs are able to process and present gut luminal antigens as they express the MHCII antigen-presentation machinery and antigens in the context of MHCII molecules [5,6,7,8,9,10]. As it remains debated whether IECs are able to provide sufficient costimulation for immunogenic T cell activation [11,12,13], it is controversial whether their function as nonprofessional APCs promotes CD4+ T cell-dependent tolerance or boosts immune responses in situ. Previous observations obtained mainly from in vitro or ex vivo studies might not reflect the more complex situation in vivo [14,15,16]

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