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P089 Extensive characterisation of cellular sources of IL-22BP in inflammatory bowel diseases indicates that T cells do not express IL-22BP

A. Fantou*1,2, A. Abidi1, L. Delbos1, J. Podevin3, A. Jarry4, M. Heslan1, J. Martin1,2, A. Bourreille5,6, R. Josien1,2

1Centre de Recherche en Transplantation et Immunologie UMR 1064, Inserm, Université de Nantes, CHU Nantes, 44000 Nantes, France, 2Laboratoire d'Immunologie, CHU Nantes, 44000 Nantes, France, 3Clinique de Chirurgie Digestive et Endocrinienne, Institut des Maladies de l'Appareil Digestif (IMAD), CHU Nantes, 44000 Nantes, France, 4CRCINA, INSERM, Université d'Angers, Université de Nantes, 44000 Nantes, France, 5Institut des Maladies de l’Appareil Digestif (IMAD), CHU Nantes, 44000 Nantes, France, 6UMR 1235, Neuropathies entériques et pathologies digestives, Université de Nantes, 44000 Nantes, France

Background

IL-22 is an epithelium-targeting cytokine of major importance in the gut. Its secretion is dramatically increased during inflammatory bowel diseases (IBD) flares. Actions of IL-22 during gut inflammation have been largely addressed, placing IL-22 as a chief cytokine to orchestrate intestinal epithelial cell (IEC) barrier functions (AMPs and mucus expression induction) and regeneration and therefore to promote mucosal healing. However, excessive actions of IL-22 could also promote tumour cell proliferation, indicating that IL-22 actions need to be tightly controlled. IL-22 binding protein (IL-22BP) is a soluble, secreted and specific inhibitor preventing IL-22 binding to its membrane IL-22R expressed on epithelial cells. Using IL-22BP-deficient rats, we demonstrated an IL-22BP-dependent inhibition of IL-22-protective functions on IEC during DSS-colitis. In human, we previously showed that IL-22BP was up-regulated in IBD inflammatory lesions and identifed dendritic cells (DCs) and eosinophils as the sources of IL-22BP. A recent report suggests that CD4+ T cells represent another cellular source of IL-22BP during IBD both in human and mice. Given these controversies, we decided to extensively revisit the cellular sources of IL-22BP.

Methods

The expression of IL-22BP mRNA was assessed by Q-PCR in FACS-sorted cells isolated from human mesenteric lymph nodes (MLN) and intestinal mucosa from IBD patients.

Results

We observed that in the gut mucosa of IBD patients, only DCs and eosinophils expressed IL-22BP mRNA. DCs from MLN also strongly expressed IL-22BP mRNA. Lamina propria and MLN CD4+ and CD8+ T cells, either of the naïve or memory/effector phenotype, did not significantly express IL-22BP mRNA, even after in vitro stimulation. Confirming these data, we did not observe any IL-22BP protein expression in CD3+ cells in colon biopsies from IBD patients analysed by immunofluorescence. We therefore generated IL-22BPGFP reporter rats and confirmed our previous data that IL-22BP expression is restricted to mononuclear phagocytes in this species. Again, T cells did not express IL-22BP in gut mucosa or lymphoid organs. Finally, we demonstrated that T cells from Il22ra2−/− rats induced similar colitis and wasting disease upon transfer in Il2rg−/− rats when compared with T cells from Il22ra2+/+ rats.

Conclusion

Taken together, our data confirm that IL-22BP expression is restricted to myeloid cells (DCs and eosinophils) and do not support a role of T cells as a source of IL-22BP in IBD.