P001 Interleukin-21 exerts pathogenic and host-protective effects in experimental models of colitis

Abstract

Background: Interleukin-21 is a T-cell derived cytokine implicated in the pathogenesis of chronic inflammatory diseases, including IBD. IL-21-receptor (IL-21R) is reported to be expressed on a diverse array of cells, including both haematopoetic and epithelial cells. In T-cells, IL-21 signaling may be a critical regulator of the balance of Th17 and regulatory (Treg) responses. However, the in vivo role of IL-21 in experimental IBD is not well understood. Methods: Using IL-21R-deficient mice, we examined the effects of IL-21 signals in complimentary models of murine IBD, including CD4+CD45RBhi T-cell transfer, Helicobacter hepaticus/anti-IL-10R, and Citrobacter rodentium infection. Results: In the Helicobacter hepaticus/anti-IL-10R model, IL-21 was pathogenic, with reduced Th17 populations and increased FOXP3+ Treg cell accumulation in the mucosa of IL-21R / animals. Similarly, in the T-cell transfer model of disease, IL-21R / T-cells were impaired in their ability to induce disease, associated with a cell-intrinsic requirement for IL-21 to regulate the balance of FOXP3+ Treg and IFN-g+ Th1 cells in the intestine. Further studies implicate a role for IL-21 in driving the expression of T-cell attracting chemokines in both these models, with studies in T-cell transfer suggesting this to be a direct T-cell dependent effect. In contrast, IL-21 was required for host protection in Citrobacter rodentium infection, with IL-21R / mice developing more severe intestinal disease, associated with greater bacterial burdens and systemic dissemination of infection. In this model, mice deficient in IL-21R were unimpaired in their Th17 responses, but developed robust Th1 responses, and an IFN-g driven immunopathology. Conclusions: IL-21 is a critical regulator of intestinal immune responses in models of IBD, exerting context specific pathogenic or host-protective effects. IL-21 may therefore be an important future therapeutic target in IBD, but its pleiotrophic effects must be considered in the development and use of drugs targeting this pathway. P002 Intestinal homeostasis is critically regulated by the transcription factor T-bet N. Powell1 *, E. Stolarczyk1, J. Lo1, J. Canavan1, E. Marks1, T. MacDonald2, G. Lord1. 1King’s College London, Experimental Immunobiology, London, 2Queen Mary University, Immunity and Infectious Diseases, London, United Kingdom