{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T18:51:31Z","timestamp":1776106291485,"version":"3.50.1"},"reference-count":76,"publisher":"Rockefeller University Press","issue":"13","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,12,21]]},"abstract":"<jats:p>Both the programmed death (PD) 1\u2013PD-ligand (PD-L) pathway and regulatory T (T reg) cells are instrumental to the maintenance of peripheral tolerance. We demonstrate that PD-L1 has a pivotal role in regulating induced T reg (iT reg) cell development and sustaining iT reg cell function. PD-L1\u2212\/\u2212 antigen-presenting cells minimally convert naive CD4 T cells to iT reg cells, showing the essential role of PD-L1 for iT reg cell induction. PD-L1\u2013coated beads induce iT reg cells in vitro, indicating that PD-L1 itself regulates iT reg cell development. Furthermore, PD-L1 enhances and sustains Foxp3 expression and the suppressive function of iT reg cells. The obligatory role for PD-L1 in controlling iT reg cell development and function in vivo is illustrated by a marked reduction in iT reg cell conversion and rapid onset of a fatal inflammatory phenotype in PD-L1\u2212\/\u2212PD-L2\u2212\/\u2212 Rag\u2212\/\u2212 recipients of naive CD4 T cells. PD-L1 iT reg cell development is mediated through the down-regulation of phospho-Akt, mTOR, S6, and ERK2 and concomitant with the up-regulation of PTEN, all key signaling molecules which are critical for iT reg cell development. Thus, PD-L1 can inhibit T cell responses by promoting both the induction and maintenance of iT reg cells. These studies define a novel mechanism for iT reg cell development and function, as well as a new strategy for controlling T reg cell plasticity.<\/jats:p>","DOI":"10.1084\/jem.20090847","type":"journal-article","created":{"date-parts":[[2009,12,14]],"date-time":"2009-12-14T21:48:09Z","timestamp":1260827289000},"page":"3015-3029","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1743,"title":["PD-L1 regulates the development, maintenance, and function of induced regulatory T cells"],"prefix":"10.1084","volume":"206","author":[{"given":"Loise M.","family":"Francisco","sequence":"first","affiliation":[{"name":"Department of Pathology, Harvard Medical School, Boston, MA 02115 1"},{"name":"Department of Pathology 2 and 3"},{"name":"Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 2 and 3"}]},{"given":"Victor H.","family":"Salinas","sequence":"additional","affiliation":[{"name":"Harvard University, Cambridge, MA 02138 4"}]},{"given":"Keturah E.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Pathology, Harvard Medical School, Boston, MA 02115 1"}]},{"given":"Vijay K.","family":"Vanguri","sequence":"additional","affiliation":[{"name":"Department of Pathology, Harvard Medical School, Boston, MA 02115 1"},{"name":"Department of Pathology 2 and 3"},{"name":"Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 2 and 3"}]},{"given":"Gordon J.","family":"Freeman","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115 5"}]},{"given":"Vijay K.","family":"Kuchroo","sequence":"additional","affiliation":[{"name":"Department of Pathology 2 and 3"},{"name":"Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 2 and 3"}]},{"given":"Arlene H.","family":"Sharpe","sequence":"additional","affiliation":[{"name":"Department of Pathology, Harvard Medical School, Boston, MA 02115 1"},{"name":"Department of Pathology 2 and 3"},{"name":"Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 2 and 3"}]}],"member":"291","published-online":{"date-parts":[[2009,12,14]]},"reference":[{"key":"2023072917334777300_bib1","doi-asserted-by":"publisher","first-page":"4351","DOI":"10.1182\/blood-2006-09-047563","article-title":"Activation of MAP kinase p38 is critical for the cell-cycle-controlled suppressor function of regulatory T cells","volume":"109","author":"Adler","year":"2007","journal-title":"Blood."},{"key":"2023072917334777300_bib2","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1002\/0470871628.ch6","article-title":"CD4+CD25+ regulatory cells from human peripheral blood express very high levels of CD25 ex vivo","volume":"252","author":"Baecher-Allan","year":"2003","journal-title":"Novartis Found. 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