{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T16:06:20Z","timestamp":1791043580645,"version":"4.1.0"},"reference-count":78,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2008,8,1]],"date-time":"2008-08-01T00:00:00Z","timestamp":1217548800000},"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":[[2008,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The costimulatory requirements required for peripheral blood T regulatory cells (Tregs) are unclear. Using cell-based artificial APCs we found that CD28 but not ICOS, OX40, 4-1BB, CD27, or CD40 ligand costimulation maintained high levels of Foxp3 expression and in vitro suppressive function. Only CD28 costimulation in the presence of rapamycin consistently generated Tregs that consistently suppressed xenogeneic graft-vs-host disease in immunodeficient mice. Restimulation of Tregs after 8\u201312 days of culture with CD28 costimulation in the presence of rapamycin resulted in &amp;gt;1000-fold expansion of Tregs in &amp;lt;3 wk. Next, we determined whether other costimulatory pathways could augment the replicative potential of CD28-costimulated Tregs. We observed that while OX40 costimulation augmented the proliferative capacity of CD28-costimulated Tregs, Foxp3 expression and suppressive function were diminished. These studies indicate that the costimulatory requirements for expanding Tregs differ from those for T effector cells and, furthermore, they extend findings from mouse Tregs to demonstrate that human postthymic Tregs require CD28 costimulation to expand and maintain potent suppressive function in vivo.<\/jats:p>","DOI":"10.4049\/jimmunol.181.4.2855","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T19:08:31Z","timestamp":1397848111000},"page":"2855-2868","source":"Crossref","is-referenced-by-count":142,"title":["CD28 Costimulation Is Essential for Human T Regulatory Expansion and Function"],"prefix":"10.1093","volume":"181","author":[{"given":"Tatiana N","family":"Golovina","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania , Philadelphia, PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Mikheeva","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania , Philadelphia, PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan M","family":"Suhoski","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania , Philadelphia, PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole A","family":"Aqui","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania , Philadelphia, PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria C","family":"Tai","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania , Philadelphia, PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochuan","family":"Shan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania , Philadelphia, PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronghua","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania , Philadelphia, PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R Robert","family":"Balcarcel","sequence":"additional","affiliation":[{"name":"BD Biosciences , San Jose, CA 95131"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Fisher","sequence":"additional","affiliation":[{"name":"BD Technologies , Research Triangle Park NC 27709"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce L","family":"Levine","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania , Philadelphia, PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard G","family":"Carroll","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania , Philadelphia, PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noel","family":"Warner","sequence":"additional","affiliation":[{"name":"BD Biosciences , San Jose, CA 95131"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce R","family":"Blazar","sequence":"additional","affiliation":[{"name":"University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl H","family":"June","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania , Philadelphia, PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James L","family":"Riley","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania , Philadelphia, PA, 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2008,8,15]]},"reference":[{"key":"2026012806183354900_R1","first-page":"8","article-title":"Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease","volume-title":"Immunol. 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Immunol.","year":"2002"},{"key":"2026012806183354900_R6","first-page":"191","article-title":"Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice","volume-title":"J. Exp. Med.","year":"2007"},{"key":"2026012806183354900_R7","first-page":"72","article-title":"Control of type 1 autoimmune diabetes by naturally occurring CD4+CD25+ regulatory T lymphocytes in neonatal NOD mice","volume-title":"Ann. NY Acad. Sci.","year":"2005"},{"key":"2026012806183354900_R8","first-page":"1455","article-title":"In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes","volume-title":"J. Exp. 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Leukocyte Biol.","year":"2004"},{"key":"2026012806183354900_R37","first-page":"2320","article-title":"4-1BB costimulation is required for protective anti-viral immunity after peptide vaccination","volume-title":"J. Immunol.","year":"2000"},{"key":"2026012806183354900_R38","first-page":"8891","article-title":"Mechanisms involved in synergistic anticancer immunity of anti-4-1BB and anti-CD4 therapy","volume-title":"Cancer Res.","year":"2007"},{"key":"2026012806183354900_R39","first-page":"3755","article-title":"In vivo triggering through 4-1BB enables Th-independent priming of CTL in the presence of an intact CD28 costimulatory pathway","volume-title":"J. Immunol.","year":"2002"},{"key":"2026012806183354900_R40","first-page":"7295","article-title":"Ex vivo expansion of CD4+CD25+FoxP3+ T regulatory cells based on synergy between IL-2 and 4-1BB signaling","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012806183354900_R41","first-page":"3029","article-title":"Immune suppression or enhancement by CD137 T cell costimulation during acute viral infection is time dependent","volume-title":"J. Clin. Invest.","year":"2007"},{"key":"2026012806183354900_R42","first-page":"89","article-title":"Engagement of the CD137 (4-1BB) costimulatory molecule inhibits and reverses the autoimmune process in collagen-induced arthritis and establishes lasting disease resistance","volume-title":"Immunology","year":"2004"},{"key":"2026012806183354900_R43","first-page":"230","article-title":"CD137-mediated T cell co-stimulation terminates existing autoimmune disease in SLE-prone NZB\/NZW F1 mice","volume-title":"Ann. NY Acad. Sci.","year":"2003"},{"key":"2026012806183354900_R44","first-page":"973","article-title":"Foxp3+ regulatory T cells promiscuously accept thymic signals critical for their development","volume-title":"Proc. Natl. Acad. Sci. 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Immun.","year":"2007"},{"key":"2026012806183354900_R49","first-page":"774","article-title":"ICOS controls the pool size of effector-memory and regulatory T cells","volume-title":"J. Immunol.","year":"2008"},{"key":"2026012806183354900_R50","first-page":"1018","article-title":"Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412","volume-title":"N. Engl. J. Med.","year":"2006"},{"key":"2026012806183354900_R51","first-page":"981","article-title":"Engineering artificial antigen-presenting cells to express a diverse array of co-stimulatory molecules","volume-title":"Mol. Ther.","year":"2007"},{"key":"2026012806183354900_R52","first-page":"166","article-title":"CD28 and inducible costimulatory protein Src homology 2 binding domains show distinct regulation of phosphatidylinositol 3-kinase, Bcl-xL, and IL-2 expression in primary human CD4 T lymphocytes","volume-title":"J. 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Immunol.","year":"1997"},{"key":"2026012806183354900_R66","first-page":"4571","article-title":"FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2007"},{"key":"2026012806183354900_R67","first-page":"6509","article-title":"K562\/GM-CSF vaccination reduces tumor burden, including achieving molecular remissions, in chronic myeloid leukemia (CML) patients (PTS) with residual disease on imatinib mesylate (IM)","volume-title":"J. Clin. Oncol.","year":"2006"},{"key":"2026012806183354900_R68"},{"key":"2026012806183354900_R69","first-page":"11790","article-title":"Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2002"},{"key":"2026012806183354900_R70","first-page":"259","article-title":"The Pim kinases control rapamycin-resistant T cell survival and activation","volume-title":"J. 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