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

M. Shale1, F. Powrie1, 1University of Oxford, Translational Gastroenterology, Oxford, United Kingdom

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-γ+ 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-γ driven immunopathology.

Conclusion

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.