Research Article: Innate CD8αα+ cells promote ILC1-like intraepithelial lymphocyte homeostasis and intestinal inflammation

Date Published: July 10, 2019

Publisher: Public Library of Science

Author(s): Ali Nazmi, Kristen L. Hoek, Michael J. Greer, Maria B. Piazuelo, Nagahiro Minato, Danyvid Olivares-Villagómez, Hiroyasu Nakano.


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.

Partial Text

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 [1–3], 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 [4–9]. Lately, it has been recognized that the IEL compartment also harbors TCRneg lymphoid cells with critical roles in mucosal immune responses [3]. The great majority of TCRneg IEL is composed of cells expressing intracellular CD3γ, which can be divided in CD8αα+ or CD8αα- IEL [10]. TCRnegCD8αα+ IEL, also referred to as innate CD8α (iCD8α) cells, have been previously characterized by our group both in mice and humans [11]. iCD8α cells possess a chemokine and cytokine signature, antigen processing capabilities, and other functions such as bacteria uptake, that suggest that these cells are important during early immune responses [11]. Other TCRneg IEL resemble innate lymphoid cells (ILC) with differential expression of the natural cytotoxicity receptor NKp46 [12–14]. Although their function is not completely understood, NKp46+NK1.1+ IEL have been shown to promote disease development in the anti-CD40 model of colitis [12].

Osteopontin is known to be widely expressed in the intestinal mucosa of ulcerative colitis and Crohn’s disease patients, and in the latter group, osteopontin plasma levels are increased in comparison to control individuals [26, 34], suggesting an involvement of this molecule in the pathology of inflammatory bowel diseases. However, the role of osteopontin in mouse models of intestinal inflammation is controversial. In the DSS model of colitis, reports vary about the role of osteopontin, either as a pro or anti-inflammatory factor [23, 34–36]. Moreover, in the trinitrobenzene sulphonic acid-induced model of colitis, osteopontin-deficient mice fare better than wild type animals, suggesting a pro-inflammatory role for this cytokine [37]. In contrast, in the IL-10-deficiency model of spontaneous intestinal inflammation, IL-10-/-Spp-1-/- mice develop disease faster than IL-10-/- control mice [36]. Finally, adoptive transfer of naïve CD62LhiCD4+ T cells into Rag-2-/-Spp-1-/- mice resulted in less chronic colitis than Rag-2-/- recipient mice [38]. How to reconcile these diverse observations? It is possible that the impact of osteopontin varies depending on the primary cell populations responsible for disease induction or the disease stage. For example, here we propose that iCD8α cells, via osteopontin, promote the survival of pro-inflammatory NKp46+NK1.1+ IEL impacting the outcome of acute colitis, whereas in other disease models osteopontin may differentially influence acute and chronic inflammation [23]. Therefore, dissecting how osteopontin affects different branches of the mucosal immune system during steady state levels and inflammatory processes is of critical relevance to increase our understanding of IEL biology and osteopontin function, as well as the impact of this cytokine in diseases such as ulcerative colitis and Crohn’s disease.