CMTM6 DEFICIENCY PROMOTES COLITIS BY REGULATING GROUP 3 INNATE LYMPHOID CELLS

Background
Ulcerative colitis (UC) is a chronic relapsing inflammatory disease, characterized by a dysregulated innate and adaptive immune response to gut microbiota. Innate lymphoid cell (ILC) 3 could promote epithelial repair through IL-22 production. CMTM6 is a membrane protein of a gene family participates in immune regulation. Recent report showed it could modulate some immune chectpoints, like PD-L1 and CD58, which are critcal for anti-tumor immune response. However, its role in colitis remains unknown.
Methods
The expression of CMTM6 during colitis was characterized using the Cmtm6-EGFP reporter mice by flow cytometry. The function of CMTM6 in colitis was demonstrated using a dextran sulfate sodium (DSS)-induced colitis mice model by Hematoxylin and Eosin (HE）staining and quantitative PCR (qPCR). The lamina propria lymphocytes (LPL) were isolated and analyzed by flow cytometry to address the change in mucosal immune response.
Results
The expression of CMTM6 was increased both in human inflamed UC mucosa and in DSS-induced mice colon. Moreover, the increased CMTM6 had a higher distribution in CD45⁺ cells than CD45^- cells. Further analysis of the expression of CMTM6 in different immune cells in the lamina propria showed that it was highly expressed in ILCs population and further increased during colitis. Using the Cmtm6 knock out (KO) mice, we demonstrated that loss of Cmtm6 promoted the development of colitis and induced more sever inflammation, including decreased body weight and colon length, increased histological score, and more pro-inflammatory cytokines in the colon tissue. The LPL immune cells analysis showed that Cmtm6 deficiency mainly resulted in decreased ILC3 population. The Cmtm6 KO mice also exhibited reduced IL-22 and IL-22-dependent antimicrobial peptides in the gut. In addition, CMTM6 expression was required for steady-state ILC3-derived IL-22 production. Furthermore, antibiotic treatment abrogated the impact of CMTM6 on colitis, indicating the role of CMTM6 in colitis is dependent on gut mocrobiota.
Conclusion
Together, we found that CMTM6 is highly expressed in ILC population and increased during colitis. Genetic ablation of Cmtm6 resulted in exacerbated colitis, decreased ILC3 population, and down-regulated IL22 expression. Thus, CMTM6 might inhibit colitis through regulating ILC3 function to maintain intestinal homeostasis and might be a potential therapeutic target for intervention in UC.