An Exploration of the Effects of Milk-Derived Osteopontin on the Development of Intestinal Intraepithelial Lymphocytes

Abstract

Bioactive breastmilk proteins are critical for infant development. One such protein, osteopontin, is known to play roles in the development of the brain and the intestinal epithelium; however, its impact on the development of the intestinal immune system is not yet known. As osteopontin is critical for the homeostasis of intestinal intraepithelial lymphocytes (IEL) in adult mice, the distribution and effector function of these cells were investigated in mice raised by osteopontin-sufficient and osteopontin-deficient dams. Several mouse models of osteopontin-deficient breastmilk were utilized, including a MMTV-Cre+/-Spp1fl/- model (with Cre recombinase under the control of the mouse mammary tumor virus long terminal repeat promoter), a Spp1-/- model, and a cross-fostered model in which pups birthed by Spp1+/- dams were raised by Spp1-/- dams. Across models, mice raised by osteopontin-deficient dams displayed alterations in the IEL compartment, with a decreased proportion of cell types expressing CD8αα, an alternate form of the CD8 co-receptor. Some populations of these cells also displayed alterations in their expression of effector molecules, including CD314 and CD107a. Despite these differences, mice raised by osteopontin-deficient dams did not display an increased susceptibility to dextran sodium sulfate-induced colitis or to infection by Citrobacter rodentium. However, mice raised by osteopontin-deficient dams did display alterations in the intestinal microbiota beginning as early as three weeks of age, characterized by increased prevalence of Clostridium and Akkermansia and decreased prevalence of Prevotella. Alterations in the IEL compartment and the intestinal microbiota lasted into adulthood (seven or eight weeks of age), indicating that early life osteopontin exposure has long-lasting implications on the intestinal immune system and the intestinal microbiota.