CD1d-mediated lipid presentation by CD11c+ cells regulates intestinal homeostasis.

Julia Sáez De Guinoa,Carles Ubeda,Patricia Barral,David Kipling,Deborah Dunn‐Walters,Mauro Gaya,Rebeca Jimeno,María José Garzón

doi:10.15252/embj.201797537

Abstract

Intestinal homeostasis relies on a continuous dialogue between the commensal bacteria and the immune system. Natural killer T (NKT) cells, which recognize CD1d‐restricted microbial lipids and self‐lipids, contribute to the regulation of mucosal immunity, yet the mechanisms underlying their functions remain poorly understood. Here, we demonstrate that NKT cells respond to intestinal lipids and CD11c+ cells (including dendritic cells (DCs) and macrophages) are essential to mediate lipid presentation within the gut ultimately controlling intestinal NKT cell homeostasis and activation. Conversely, CD1d and NKT cells participate in the control of the intestinal bacteria composition and compartmentalization, in the regulation of the IgA repertoire and in the induction of regulatory T cells within the gut. These changes in intestinal homeostasis require CD1d expression on DC/macrophage populations as mice with conditional deletion of CD1d on CD11c+ cells exhibit dysbiosis and altered immune homeostasis. These results unveil the importance of CD11c+ cells in controlling lipid‐dependent immunity in the intestinal compartment and reveal an NKT cell–DC crosstalk as a key mechanism for the regulation of gut homeostasis.

Highlights

The mammalian intestine contains a highly complex mixture of microorganisms that perform many metabolic functions and are critical for the establishment of tissue homeostasis
INKT cells found in gutassociated tissues (including mesenteric lymph nodes and small intestinal (SI) and colonic lamina propria (LP)) did express GFP, indicating that iNKT cells in those tissues are receiving T-cell receptor (TCR) stimulation which could possibility originate from the recognition of commensal-derived lipids
Intestinal Natural killer T (NKT) cells play a central role in the regulation of mucosal immunity, and dysregulation of CD1d expression and NKT cell activation have been associated with the development of intestinal inflammation in mice and humans (Dowds et al, 2015)

Summary

Introduction

The mammalian intestine contains a highly complex mixture of microorganisms that perform many metabolic functions and are critical for the establishment of tissue homeostasis. It is well established that the adaptive immune system has continuous interactions with commensal bacteria to regulate the population of T-helper 17 (Th17) cells. The mechanisms by which commensals control immune cell numbers and function are complex and poorly understood, but in recent years it has become apparent that the T-cell receptor (TCR)-dependent recognition of commensal-derived antigens by intestinal T cells is a central step in the regulation of intestinal immunity. Intestinal Th17 cells are induced in response to SFB colonization and the MHC-II-dependent presentation of SFB antigens by intestinal DCs is crucial for Th17 induction (Goto et al, 2014; Yang et al, 2014). Antigen presentation by intestinal DCs is essential to maintain intestinal homeostasis as mice with conditional deletion of MHC-II in conventional DCs develop microbial-dependent intestinal inflammation (Loschko et al, 2016)

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Conclusion