{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T10:39:04Z","timestamp":1773657544947,"version":"3.50.1"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2005,9,1]],"date-time":"2005-09-01T00:00:00Z","timestamp":1125532800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2005,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The small GTPase Rap1 is transiently activated during TCR ligation and regulates integrin-mediated adhesion. To understand the in vivo functions of Rap1 in regulating T cell immune responses, we generated transgenic (Tg) mice, which express the active GTP-bound mutant Rap1E63 in their T lymphocytes. Although Rap1E63-Tg T cells exhibited increased LFA-1-mediated adhesion, ERK1\/2 activation and proliferation of Rap1E63-Tg CD4+ T cells were defective. Rap1E63-Tg T cells primed in vivo and restimulated with specific Ag in vitro, exhibited reduced proliferation and produced reduced levels of IL-2. Rap1E63-Tg mice had severely deficient T cell-dependent B cell responses, as determined by impaired Ig class switching. Rap1E63-Tg mice had an increased fraction of CD4+CD103+ regulatory T cells (Treg), which exhibited enhanced suppressive efficiency as compared with CD4+CD103+ Treg from normal littermate control mice. Depletion of CD103+ Treg significantly restored the impaired responses of Rap1E63-Tg CD4+ T cells. Thus Rap1-GTP is a negative regulator of Th cell responses and one mechanism responsible for this effect involves the increase of CD103+ Treg cell fraction. Our results show that Rap1-GTP promotes the generation of CD103+ Treg and may have significant implications in the development of strategies for in vitro generation of Treg for the purpose of novel immunotherapeutic approaches geared toward tolerance induction.<\/jats:p>","DOI":"10.4049\/jimmunol.175.5.3133","type":"journal-article","created":{"date-parts":[[2014,4,24]],"date-time":"2014-04-24T13:44:04Z","timestamp":1398347044000},"page":"3133-3139","source":"Crossref","is-referenced-by-count":29,"title":["Rap1-GTP Is a Negative Regulator of Th Cell Function and Promotes the Generation of CD4+CD103+ Regulatory T Cells In Vivo"],"prefix":"10.1093","volume":"175","author":[{"given":"Lequn","family":"Li","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA 02115"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca J","family":"Greenwald","sequence":"additional","affiliation":[{"name":"Department of Pathology, Harvard Medical School and Brigham and Women\u2019s Hospital , Boston, MA 02115"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esther M","family":"Lafuente","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA 02115"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitrios","family":"Tzachanis","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA 02115"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alla","family":"Berezovskaya","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA 02115"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gordon J","family":"Freeman","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA 02115"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arlene H","family":"Sharpe","sequence":"additional","affiliation":[{"name":"Department of Pathology, Harvard Medical School and Brigham and Women\u2019s Hospital , Boston, MA 02115"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vassiliki A","family":"Boussiotis","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA 02115"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2005,9,1]]},"reference":[{"key":"2025032705421094200_R1","first-page":"77","volume-title":"Cell","year":"1989"},{"key":"2025032705421094200_R2","first-page":"3475","volume-title":"EMBO J.","year":"1993"},{"key":"2025032705421094200_R3","first-page":"169","volume-title":"Science","year":"1990"},{"key":"2025032705421094200_R4","first-page":"554","volume-title":"Nature","year":"1995"},{"key":"2025032705421094200_R5","first-page":"372","volume-title":"Br. 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