{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:25:34Z","timestamp":1758587134573,"version":"3.44.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Inflammatory bowel disease (IBD) is characterized by chronic, relapsing inflammation of the gastrointestinal tract. Genetic factors, including variants in T-cell activation Rho GTPase-activating protein (TAGAP), contribute to disease susceptibility and severity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A newly identified TAGAP coding variant E147K was examined by GTP hydrolysis assay. To clarify the role of TAGAP in human immune regulation, CRISPR knockout approaches were employed to study functional changes of human myeloid and T cells. Murine studies, including anti-CD3 antibody injection and CD4<jats:sup>+<\/jats:sup>CD45RB<jats:sup>hi<\/jats:sup> T cell adoptive transfer models, were conducted to assess TAGAP-mediated Th17 responses and chronic colitis severity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>IBD-risk-associated TAGAP variant E147K exhibited enhanced GTPase-activating activity. In human innate and adaptive immune cells, TAGAP restrained cell activation, migration, phagocytosis, and proinflammatory cytokine release. TAGAP deficiency led to significantly increased Th17 cell accumulation due to reduced apoptosis in the murine small intestine and exacerbated chronic intestinal inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings demonstrated the role of TAGAP in immune responses and homeostasis. The E147K variant underscores TAGAP\u2019s protective function in IBD, and further investigation is warranted to translate these insights into therapeutic strategies for autoimmune diseases.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1641365","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T09:51:17Z","timestamp":1758534677000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["TAGAP restrains myeloid and T cell activation in inflammatory bowel disease"],"prefix":"10.3389","volume":"16","author":[{"given":"Rui-Ci","family":"Lin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhifei","family":"Shao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00551","article-title":"Inflammatory bowel disease: genetics, epigenetics, and pathogenesis","volume":"6","author":"Loddo","year":"2015","journal-title":"Front Immunol"},{"key":"B2","article-title":"Environmental risk factors for inflammatory bowel disease","volume":"6","author":"Molodecky","year":"2010","journal-title":"Gastroenterol Hepatol (N Y)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2017.10.002","article-title":"T cell activation Rho GTPase activating protein (TAGAP) is upregulated in clinical and experimental arthritis","volume":"104","author":"Arshad","year":"2018","journal-title":"Cytokine"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/bph.2014.171.issue-24","article-title":"Targeting Rho-GTPases in immune cell migration and inflammation","volume":"171","author":"Biro","year":"2014","journal-title":"Br J Pharmacol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aan8799","article-title":"Regulation of thymocyte trafficking by Tagap, a GAP domain protein linked to human autoimmunity","volume":"11","author":"Duke-Cohan","year":"2018","journal-title":"Sci Signal"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/gene.2015.61","article-title":"The multiple sclerosis susceptibility genes TAGAP and IL2RA are regulated by vitamin D in CD4+ T cells","volume":"17","author":"Berge","year":"2016","journal-title":"Genes Immun"},{"key":"B7","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1093\/cei\/uxad084","article-title":"TAGAP activates Th17 cell differentiation by promoting RhoA and NLRP3 to accelerate rheumatoid arthritis development","volume":"214","author":"Sun","year":"2023","journal-title":"Clin Exp Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2014.01.019","article-title":"T-cell activation Rho GTPase-activating protein expression varies with inflammation location and severity in Crohn's disease","volume":"190","author":"Connelly","year":"2014","journal-title":"J Surg Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1097\/DCR.0b013e3182676931","article-title":"Mutation in TAGAP is protective of anal sepsis in ileocolic Crohn\u2019s disease","volume":"55","author":"Connelly","year":"2012","journal-title":"Dis colon rectum"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.1030947","article-title":"T-cell activation Rho GTPase-activating protein maintains intestinal homeostasis by regulating intestinal T helper cells differentiation through the gut microbiota","volume":"13","author":"He","year":"2023","journal-title":"Front Microbiol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2017.27","article-title":"T-cell activation RhoGTPase-activating protein plays an important role in TH17-cell differentiation","volume":"95","author":"Tamehiro","year":"2017","journal-title":"Immunol Cell Biol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1913","DOI":"10.1038\/s41467-020-15564-7","article-title":"TAGAP instructs Th17 differentiation by bridging Dectin activation to EPHB2 signaling in innate antifungal response","volume":"11","author":"Chen","year":"2020","journal-title":"Nat Commun"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/ng1617","article-title":"The t complex\u2013encoded GTPase-activating protein Tagap1 acts as a transmission ratio distorter in mice","volume":"37","author":"Bauer","year":"2005","journal-title":"Nat Genet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.82.2.315","article-title":"Functional changes in human leukemic cell line HL-60. 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