1. Interleukin-21 and the relationship with the Th1/Th17 axis Adria Carbo – Lab Meeting Presentation March 15 th 2013

2. Interleukin-21  Interleukin 21 (IL-21) is mostly produced by activated CD4+ T cells (especially Th17), T follicular helper cells and NKT cells.  IL-21 induces proliferation and increases cell survival and cytokine synthesis in T cells.  IL-21 helps to the maintenance of Th17 by acting in an autocrine fashion.  IL-21 inhibits IL-2 production and impairs Treg homeostasis  IL-21 is increased with H. pylori infection and correlates with levels of gastritis in the mouse model.  IL-21 was associated with H. pylori infection in a study of infected humans

3. MIEP and Vanderbilt University Experimental work Computational work

4. IL-21 and H. pylori wild type IL-21 null Mathematical Modeling & Pathway Analysis Flow cytometry, RT-PCR, Histopathology, Bacterial counts RESULTS

5. IL-21 and H. pylori

10. Calibration process ExperimentObjective Value Root Mean Square Error MeanError Mean Std. Deviation Experiment_2 (IL17)25.0922.5046-2.406930.692608 Experiment_3 (IFNg)1.221780.552672-0.5437560.0988712

11. In silico simulations

12. AB

14. IL-10 is upregulated in IL-21 null mice

15. Side-by-side comparison

18. Conclusions  Our results support that CD4+ are a crucial player for the development of H. pylori-associated gastritis  IL-21 is not only required for the maintenance of IL-17 but also plays an important role in the development of the IFN  response.  IL-21 is not required at the first stage of differentiation, but plays a key role in a later stage of Th17 differentiation.  IL-21 may be involved in controlling the balance of the regulatory versus effector responses during H. pylori.  Our modeling results oriented the experimental analysis and set up.  IL-21 can be a promising therapeutic target for treatment of T cell mediated diseases

19. Questions? Thanks!