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OP030 Loss of PTPN2 in dendritic cells promotes T-cell activation and expression of co-stimulatory molecules

L. Hering1*, C. Gottier1, S. Lang1, B. Becher2, G. Rogler1, M. Scharl1, M. Spalinger1

1University Hospital Zurich, Division of Gastroenterology and Hepatology, Zurich, Switzerland, 2University of Zurich, Institute of Experimental Immunologx, Zurich, Switzerland

Background

Variants within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with the development of inflammatory disorders. The role of PTPN2 in T cells and intestinal epithelial cells has been investigated in depth, but its role in dendritic cells (DCs) remains unclear. Here, we addressed whether loss of PTPN2 in DCs affects the expression of the co-stimulatory molecules and subsequently activation of T cells.

Methods

For this aim, we generated mice lacking PTPN2 specifically in DCs (PTPN2-CD11cCre mice). Using flow cytometry, we analysed spleen, mesenteric lymph nodes, and lamina propria in PTPN2-CD11cCre and their wild-type littermate controls.

Results

PTPN2-CD11cCre mice show symptoms of splenomegaly and dermatitis, as well as inflammatory infiltrations in the liver and lung in some mice. Severity of the inflammation varies between individuals, resulting in spontaneous death in some mice. PTPN2-CD11cCre mice do not differ in terms of DCs frequencies in spleen and mesenteric lymph nodes compared with their wild-type littermate controls, but we observed an increased expression of co-stimulatory molecules CD80 and CD86. In the lamina propria, however, DC frequencies were reduced, and the remaining DCs expressed reduced levels of CD80 and CD86. Of note, there was no difference regarding the expression of MHCII on CD11c+ cells between PTPN2-CD11cCre and their littermate controls. Consistent with increased expression of co-stimulatory molecules, we observed increased numbers of CD44+ effector/memory CD4+ and CD8+ T cells, as well as IFN-gamma+CD4+ T cells, indicating an enhanced T-cell activation capacity of PTPN2-deficient DCs.

Conclusion

In conclusion, our results show that PTPN2 has an important anti-inflammatory role in DCs. Loss of PTPN2 in DCs promotes T-cell activation as well as increased expression of CD80 and CD86. Furthermore, it increases the ratio between CD11b+ DC2 and CD24+DC1 in skin and lymph nodes.