Osteopontin and iCD8α cells promote intestinal intraepithelial lymphocytes homeostasis

Abstract

Intestinal intraepithelial lymphocytes (IEL) comprise a diverse population of cells residing in the epithelium at the interface between the intestinal lumen and the sterile environment of the lamina propria. Because of this anatomical location, IEL are considered critical components of intestinal immune responses. Indeed, IEL are involved in many different immunological processes ranging from pathogen control to tissue stability. However, despite their critical importance in mucosal immune responses, very little is known about the homeostasis of different IEL subpopulations. The phosphoprotein osteopontin is important for critical physiological processes, including cellular immune responses such as survival of Th17 cells and homeostasis of NK cells, among others. Because of its impact in the immune system, we investigated the role of osteopontin in the homeostasis of IEL. Here, we report that mice deficient in the expression of osteopontin exhibit reduced numbers of the IEL subpopulations TCR{gamma}{delta}+, TCR{beta}+CD4+, TCR{beta}+CD4+CD8+ and TCR{beta}+CD8+ cells in comparison to wild-type mice. For some IEL subpopulations the decrease in cells numbers could be attributed to apoptosis and reduced cell division. Moreover, we show in vitro that exogenous osteopontin stimulates the survival of murine IEL subpopulations and unfractionated IEL derived from human intestines, an effect mediated by CD44, a known osteopontin receptor. We also show that iCD8 IEL, but not TCR{gamma}{delta}+ IEL, TCR{beta}+ IEL or intestinal epithelial cells, can promote survival of different IEL populations via osteopontin, indicating an important role for iCD8 cells in the homeostasis of IEL. Key PointsO_LIOsteopontin promotes homeostasis of mouse and human IEL, mediated by its ligand CD44 C_LIO_LIiCD8 cells produce osteopontin which impacts the survival of other IEL C_LIO_LILack of osteopontin renders mice susceptible to intestinal inflammation C_LI