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In this study, we found that cluster of differentiation 226 (CD226) gene knockout (KO) led to more severe atopic dermatitis (AD)\u2010related skin pathologies and bowel abnormalities in a 2,4\u2010dinitrochlorobenzene (DNCB)\u2010induced AD\u2010like mouse model. Following DNCB administration, the expression of CD226 was elevated in intestinal mucosal tissues, including group 3 innate lymphoid cells (ILC3s) and CD4<jats:sup>+<\/jats:sup> T cells of Peyer's patches (PPs). CD226 deficiency led to an overactive intestinal immune response in the AD\u2010like mice, as evidenced by increased inflammation and Th1\/Th2\u2010related cytokine levels as well as increased Paneth cell numbers and antimicrobial peptide (AMP) expression, which was likely due to the higher interleukin (IL)\u201022 production in the lamina propria. Additionally, CD226 deficiency increased the production of IL\u20104 and IL\u201017 in mesenteric lymph nodes as well as the number of PPs and expression of immunoglobulin (Ig) A in B cells. Moreover, insufficient expression of CD226 affected the characterization of intraepithelial and lamina propria lymphocytes in the intestinal mucosa. Finally, the number of PPs was increased in CD4<jats:sup>+<\/jats:sup> T cell\u2010specific CD226 KO and regulatory T (Treg) cell\u2010specific CD226 KO mice; thus, loss of CD226 in Treg cells resulted in impaired Treg cell\u2010suppressive function. Therefore, our findings indicate that CD226 deficiency alters intestinal immune functionality in inflammatory diseases.<\/jats:p>","DOI":"10.1111\/imm.13640","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T09:55:28Z","timestamp":1679306128000},"page":"431-446","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<scp>CD226<\/scp> deficiency exacerbated intestinal immune dysregulation in mice with dinitrochlorobenzene\u2010induced atopic dermatitis"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4351-6480","authenticated-orcid":false,"given":"Tingting","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Immunology Fourth Military Medical University  Xi'an Shaanxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Qiao","sequence":"additional","affiliation":[{"name":"Institute of Medical 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