Role of iNKT cells and EBI3 in experimental colitis

Murine models of human inflammatory bowel disease (IBD) have largely contributed to new therapeutic modalities in recent years. Oxazolone colitis is a recently developed model of ulcerative colitis, a particular form of IBD, and has been linked to the activity of invariant natural killer T (iNKT) cells. iNKT cells recognize lipid antigens by virtue of the MHC I-homologue CD1d, and regulate various types of immune functions and have a role in several immunopathologies, although their exact mode of action in these models is still enigmatic. Epstein Barr virus-induced gene 3 (EBI3) is a novel heterodimeric cytokine overexpressed in ulcerative colitis, and mice with a targeted deletion of ebi3 are protected from oxazolone colitis. Additionally, these mice also have substantially diminished numbers of iNKT cells. The aim of the current proposal is to elucidate the exact role of iNKT cells in oxazolone colitis as well as the relationship of EBI3 and iNKT cells. Besides the analysis of the kinetics of activation and localization of iNKT cells in oxazolone colitis, we plan several series of adoptive transfer experiments to identify the role of EBI3 and iNKT cells in oxazolone colitis. Particular emphasis will be put on the identification of developmental functions of EBI3 on iNKT cells. Furthermore, we will attempt to gain clues on alternative heterodimeric binding partners of EBI3, since the currently known (IL-27 p28 and IL-12 p35) might not account for the phenotype of EBI3-/- mice. The proposed experiments should lead to a thorough understanding of iNKT cell function in oxazolone colitis, and elucidate pathways of iNKT cell regulation by EBI3. Based on the overexpression of EBI3 in human ulcerative colitis, this could break new ground for future therapies of this debilitating disease.