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P094. CCL25/CCR9 interactions promote the induction and function of iNKT cells in oxazolone-induced colitis in mice

S. Zhu, Y. Bing, B. Xia, R. Zhou, Y. Zhu, Zhongnan Hospital of Wuhan University, Gastroenterology/Hepatology, Wuhan, China

Background

Natural killer T (NKT) cells share phenotypic and functional properties with both conventional natural killer cells and T cells. These cells might have an important role in the pathogenesis of ulcerative colitis (UC). The interaction of chemokine ligand 25 (CCL25) with chemokine receptor 9 (CCR9) is involved in gut-specific migration of leukocytes and induces regulatory T cells (Tregs) to migrate to the intestine in chronic ileitis.

Methods

In UC patients, we observed that NKT receptor CD161, CCL25 and CCR9 expression levels by quantitative real-time polymerase chain reaction (qRT-PCR). We used a murine model of oxazolone-induced colitis to investigate the potential regulatory roles of CCL25/CCR9 interactions in NKT cells and examined the underlying mechanisms. After colitis was induced in mice, we evaluated body weight, survival rate, clinical score, histological score, colon length and myeloperoxidase (MPO) activity. The mRNA expression levels of NK1.1, CCL25 and CCR9 in mice were examined by qRT-PCR. We performed ELISA assays to evaluate the pro-inflammatory cytokines. The CCR9 expression on Type I and invariant NKT (iNKT) cells, and the iNKT cells chemotaxis are observed according to flow cytometry.

Results

We observed that NKT receptor CD161, CCL25 and CCR9 expression levels were significantly increased in UC patients. After colitis was induced in mice, we evaluated body weight, survival rate, clinical score, histological score, colon length and myeloperoxidase (MPO) activity. The mRNA expression levels of NK1.1, CCL25 and CCR9 in mice were similar to expression levels in UC patients. The production of pro-inflammatory cytokines was significantly increased, especially interleukin 4 (IL-4), IL-10, and IL-13. According to flow cytometry, we observed significantly increased CCR9 expression on Type I and invariant NKT (iNKT) cells, and increased iNKT cells chemotaxis. Furthermore, we found an increased iNKT population and enhanced chemotaxis during oxazolone-induced colitis.

Conclusion

Our study suggests that CCL25/CCR9 interactions promote the induction and function of iNKT cells through changes in dendritic cell (DC) subpopulations. These findings have important implications for human inflammatory bowel disease (IBD) treatment and suggest a role for CCR9 inhibitors.