Innate CD8αα+ cells promote ILC1-like intraepithelial lymphocyte homeostasis and intestinal inflammation.

Ali Nazmi,Maria B Piazuelo,Nagahiro Minato,Michael J Greer,Kristen L Hoek,Danyvid Olivares-Villagómez,Hiroyasu Nakano

doi:10.1371/journal.pone.0215883

Abstract

Innate CD8αα+ cells, also referred to as iCD8α cells, are TCR-negative intraepithelial lymphocytes (IEL) possessing cytokine and chemokine profiles and functions related to innate immune cells. iCD8α cells constitute an important source of osteopontin in the intestinal epithelium. Osteopontin is a pleiotropic cytokine with diverse roles in bone and tissue remodeling, but also has relevant functions in the homeostasis of immune cells. In this report, we present evidence for the role of iCD8α cells in the homeostasis of TCR-negative NKp46+NK1.1+ IEL (ILC1-like). We also show that the effect of iCD8α cells on ILC1-like IEL is enhanced in vitro by osteopontin. We show that in the absence of iCD8α cells, the number of NKp46+NK1.1+ IEL is significantly reduced. These ILC1-like cells are involved in intestinal pathogenesis in the anti-CD40 mouse model of intestinal inflammation. Reduced iCD8α cell numbers results in a milder form of intestinal inflammation in this disease model, whereas treatment with osteopontin increases disease severity. Collectively, our results suggest that iCD8α cells promote survival of NKp46+NK1.1+ IEL, which significantly impacts the development of intestinal inflammation.

Highlights

Intestinal intraepithelial lymphocytes (IEL) constitute a population of cells dwelling interspersed in the monolayer of intestinal epithelial cells (IEC), and represent a unique immunological compartment in the intestines
Using mice with reduced innate CD8α (iCD8α) cell numbers, we show that iCD8α cells have a critical role in NKp46+NK1.1+ IEL survival, which is partly mediated by osteopontin, and that disruption of NKp46+NK1.1+ IEL homeostasis impacts the development of inflammatory processes in the intestines
E8I-/-Rag2-/- mice presented with lower numbers of total CD45+ IEL, which may account for the reduction in iCD8α cells (Fig 1B), and a corresponding increase in the frequencies of CD45+CD8αneg IEL (Fig 1C)

Summary

Introduction

Intestinal intraepithelial lymphocytes (IEL) constitute a population of cells dwelling interspersed in the monolayer of intestinal epithelial cells (IEC), and represent a unique immunological compartment in the intestines. Because of their anatomical location, IEL are considered to be the first line of defense against the enormous antigenic stimulus present in the lumen of the intestines. T cell receptor αβ+ and γδ+ cells constitute the great majority of IEL [1,2,3], and these cells possess many and varied roles during mucosal immune responses and inflammatory processes, ranging from specific immunity against pathogens, tissue repair and homeostasis of the intestinal epithelium [4,5,6,7,8,9]. It has been recognized that the IEL compartment.

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Conclusion