Innate CD8 alpha alpha(+) cells promote ILC1-like intraepithelial lymphocyte homeostasis and intestinal inflammation

Abstract

Innate CD8 alpha alpha(+) cells, also referred to as iCD8 alpha cells, are TCR-negative intraepithelial lymphocytes (IEL) possessing cytokine and chemokine profiles and functions related to innate immune cells. iCD8 alpha 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 iCD8 alpha cells in the homeostasis of TCR-negative NKp46(+)NK1.1(+)IEL (ILC1-like). We also show that the effect of iCD8 alpha cells on ILC1-like IEL is enhanced in vitro by osteopontin. We show that in the absence of iCD8 alpha 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 iCD8 alpha 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 iCD8 alpha cells promote survival of NKp46(+)NK1.1(+)IEL, which significantly impacts the development of intestinal inflammation.