Osteopontin promotes survival of intestinal intraepithelial lymphocytes and protects against colitis

Abstract

Abstract Intestinal intraepithelial lymphocytes (IEL) comprise a diverse population of cells that reside in the epithelium at the interface between the contents of 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, maintenance of IEL homeostasis is incompletely understood. In this report, we present evidence that osteopontin, a glycophosphoprotein with diverse roles in biomineralization, cell-mediated immunity, and inflammation, is important for maintaining normal levels of IEL. Mice in which the osteopontin gene (Spp-1) is disrupted present decreased levels of IEL subtypes, such as TCRαβ and TCRγδ IEL in the intestine, an effect not observed for lymphocytes in other immune compartments such as spleen or lamina propria, indicating an epithelium-specific effect. In vitro experiments show that mouse and human IEL survival is improved by culture with recombinant osteopontin. In vivo and in vitro IEL survival studies show that CD44, a ligand for osteopontin, is critical for the capacity of osteopontin to promote IEL survival. Adoptive transfer of total T cells (including Tregs) from wild type mice into Spp-1−/−Rag-2−/− mice results in the development of exacerbated intestinal inflammation, as compared with Rag-2−/− recipient mice. Further analyses show that osteopontin-deficiency results in decreased survival of Foxp3-expressing T cells. These findings support osteopontin’s critical role in IEL homeostasis and make it a potential target for curbing intestinal inflammation.