Protective Role of Foxo3a in the Regulatory T Cells and Dendritic Cells of IL-10-Deficient Mice

Abstract

Inflammatory bowel disease (IBD) affects about 322,600 Canadians and is expected to rise to 470,000 Canadians by 2035. Crohn’s disease (CrD) is a severe form of IBD, and in acute cases requires hospitalization and surgical intervention. CrD is mediated by complex gene-environment interactions where many genetic and environmental factors are associated with the disease. Current treatments manage the symptoms, but treatments that tackle the underlying cause are needed to improve patient outcomes. In this study, a novel mouse model for CrD was developed in which a susceptibility allele (IL-10) and a progression allele (Foxo3a) are deactivated. Foxo3a-/- IL-10-/- mice spontaneously develop a Crohn’s-like phenotype consistent with CrD in humans. Regulatory T cells (Tregs) play an important role in mediating immune homeostasis and peripheral self-tolerance, thus playing a key role in preventing chronic inflammation. DCs are important in regulating the response to the gut microbiota. This study demonstrates that Foxo3a plays a key role in maintaining the differentiation, stability, and suppressive capacity of Tregs in IL-10-deficient mice. This study demonstrates that Foxo3a plays a role in the in vitro differentiation of moDCs. Additionally, the results of this study indicate that excessive cytokine production by DCs can be inhibited through a variety of pathways. Foxo3a also regulates a key checkpoint in Treg differentiation and stability in IL-10-deficient mice. In sum, Foxo3a and IL-10 play antagonistic roles that maintain proper Treg and DC function and development. This study reveals novel pathways that can be targeted for therapeutic intervention in IBD.