{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:55:07Z","timestamp":1790834107206,"version":"4.1.0"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2016,9,1]],"date-time":"2016-09-01T00:00:00Z","timestamp":1472688000000},"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":[[2016,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>A successful pregnancy depends on the maintenance of tolerance at the fetal\u2013maternal interface; strong inflammation in the placental bed is generally associated with adverse fetal outcomes. Among the mechanisms that foster tolerance and limit inflammation, the fetal immune system favors Th2 or regulatory responses over Th1 responses. The unintended consequence of this functional program is high susceptibility to infections. Human V\u03b42 T cells mount innate-like responses to a broad range of microorganisms and are poised for Th1 responses before birth. In infants they likely play a key role in protection against pathogens by exerting early Th1 effector functions, improving function of other innate cells, and promoting Th1 polarization of adaptive responses. However, their propensity to release Th1 mediators may require careful regulation during fetal life to avoid exaggerated proinflammatory responses. We investigated molecules with the potential to act as a rheostat for fetal V\u03b42 cells. Programmed death 1 (PD1) is a negative regulator of T cell responses and a determinant of tolerance, particularly at the fetal\u2013maternal interface. Neonatal V\u03b42 cells upregulate PD1 shortly after activation and, unlike their adult counterparts, express this molecule for at least 28 d. Engagement of PD1 by one of its ligands, PDL1, effectively dampens TCR-mediated responses (TNF-\u03b1 production and degranulation) by neonatal V\u03b42 cells and may thus help maintain their activity within safe limits. PD1 expression by neonatal V\u03b42 cells is inversely associated with promoter DNA methylation. Prolonged PD1 expression may be part of a functional program to control V\u03b42 cell inflammatory responses during fetal life.<\/jats:p>","DOI":"10.4049\/jimmunol.1600284","type":"journal-article","created":{"date-parts":[[2016,7,30]],"date-time":"2016-07-30T01:39:46Z","timestamp":1469842786000},"page":"1884-1892","source":"Crossref","is-referenced-by-count":29,"title":["Prolonged PD1 Expression on Neonatal V\u03b42 Lymphocytes Dampens Proinflammatory Responses: Role of Epigenetic Regulation"],"prefix":"10.1093","volume":"197","author":[{"given":"Haoting","family":"Hsu","sequence":"first","affiliation":[{"name":"Institute of Human Virology, University of Maryland , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Boudova","sequence":"additional","affiliation":[{"name":"Division of Malaria Research at the Institute for Global Health, School of Medicine, University of Maryland , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Godfrey","family":"Mvula","sequence":"additional","affiliation":[{"name":"Blantyre Malaria Project, University of Malawi College of Medicine , Blantyre 3,","place":["Malawi"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3029-9579","authenticated-orcid":false,"given":"Titus H","family":"Divala","sequence":"additional","affiliation":[{"name":"Blantyre Malaria Project, University of Malawi College of Medicine , Blantyre 3,","place":["Malawi"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2505-0904","authenticated-orcid":false,"given":"Randy G","family":"Mungwira","sequence":"additional","affiliation":[{"name":"Blantyre Malaria Project, University of Malawi College of Medicine , Blantyre 3,","place":["Malawi"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9918-5508","authenticated-orcid":false,"given":"Christopher","family":"Harman","sequence":"additional","affiliation":[{"name":"Obstetrics, Gynecology and Reproductive Health, University of Maryland , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam K","family":"Laufer","sequence":"additional","affiliation":[{"name":"Division of Malaria Research at the Institute for Global Health, School of Medicine, University of Maryland , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C David","family":"Pauza","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, University of Maryland , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiana","family":"Cairo","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, University of Maryland , Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,9,1]]},"reference":[{"key":"2025030617480293600_r1","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1111\/aji.12083","article-title":"Fetal regulatory T cells and peripheral immune tolerance in utero: implications for development and disease","volume":"69","author":"Burt","year":"2013","journal-title":"Am. J. Reprod. Immunol."},{"key":"2025030617480293600_r2","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.it.2009.09.002","article-title":"Neonatal immunity: faulty T-helpers and the shortcomings of dendritic cells","volume":"30","author":"Zaghouani","year":"2009","journal-title":"Trends Immunol."},{"key":"2025030617480293600_r3","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1007\/s12026-013-8439-2","article-title":"Neonatal immunology: responses to pathogenic microorganisms and epigenetics reveal an \u201cimmunodiverse\u201d developmental state","volume":"57","author":"Adkins","year":"2013","journal-title":"Immunol. Res."},{"key":"2025030617480293600_r4","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.it.2014.04.007","article-title":"Ontogeny of early life immunity","volume":"35","author":"Dowling","year":"2014","journal-title":"Trends Immunol."},{"key":"2025030617480293600_r5","doi-asserted-by":"crossref","first-page":"574","DOI":"10.3389\/fimmu.2014.00574","article-title":"Preterm birth, intrauterine infection, and fetal inflammation","volume":"5","author":"Kemp","year":"2014","journal-title":"Front. 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Immunol."},{"key":"2025030617480293600_r15","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1007\/s10875-005-4080-8","article-title":"Complementary function of \u03b3\u03b4 T-lymphocytes and dendritic cells in the response to isopentenyl-pyrophosphate and lipopolysaccharide antigens","volume":"25","author":"Martino","year":"2005","journal-title":"J. Clin. Immunol."},{"key":"2025030617480293600_r16","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1007\/s00262-010-0839-8","article-title":"(E)-4-hydroxy-3-methyl-but-2 enyl pyrophosphate-stimulated V\u03b39V\u03b42 T cells possess T helper type 1-promoting adjuvant activity for human monocyte-derived dendritic cells","volume":"59","author":"Dunne","year":"2010","journal-title":"Cancer Immunol. Immunother."},{"key":"2025030617480293600_r17","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1111\/j.1365-2567.2007.02784.x","article-title":"V\u03b42 T-lymphocyte responses in cord blood samples from Italy and C\u00f4te d\u2019Ivoire","volume":"124","author":"Cairo","year":"2008","journal-title":"Immunology"},{"key":"2025030617480293600_r18","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1189\/jlb.0910501","article-title":"IL-23R and TCR signaling drives the generation of neonatal V\u03b39V\u03b42 T cells expressing high levels of cytotoxic mediators and producing IFN-\u03b3 and IL-17","volume":"89","author":"Moens","year":"2011","journal-title":"J. Leukoc. Biol."},{"key":"2025030617480293600_r19","doi-asserted-by":"crossref","first-page":"3979","DOI":"10.4049\/jimmunol.153.9.3979","article-title":"TCR usage and functional capabilities of human \u03b3\u03b4 T cells at birth","volume":"153","author":"Morita","year":"1994","journal-title":"J. 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Immunol."},{"key":"2025030617480293600_r23","doi-asserted-by":"crossref","first-page":"6313","DOI":"10.1016\/j.vaccine.2007.06.039","article-title":"Robust \u03b3\u03b4+ T cell expansion in infants immunized at birth with BCG vaccine","volume":"25","author":"Mazzola","year":"2007","journal-title":"Vaccine"},{"key":"2025030617480293600_r24","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1111\/j.1399-3038.2005.00329.x","article-title":"Influence of bacillus Calmette-Gu\u00e8rin vaccination at birth and 2 months old age on the peripheral blood T-cell subpopulations [gamma\/delta (\u03b3\u03b4) and alpha-beta (\u03b1\u03b2) T cell]","volume":"16","author":"Ta\u015ftan","year":"2005","journal-title":"Pediatr. 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Immunol."},{"key":"2025030617480293600_r28","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1016\/j.ajpath.2013.02.014","article-title":"B7h (ICOS-L) maintains tolerance at the fetomaternal interface","volume":"182","author":"Riella","year":"2013","journal-title":"Am. J. Pathol."},{"key":"2025030617480293600_r29","doi-asserted-by":"crossref","first-page":"25","DOI":"10.4103\/2319-4170.143511","article-title":"Role of PD1\/PDL1 pathway, and Th17 and Treg cells in maternal tolerance to the fetus","volume":"38","author":"Tripathi","year":"2015","journal-title":"Biomed. J."},{"key":"2025030617480293600_r30","doi-asserted-by":"crossref","first-page":"9331","DOI":"10.1073\/pnas.0710441105","article-title":"Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells","volume":"105","author":"Wang","year":"2008","journal-title":"Proc. Natl. Acad. Sci. 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Immunol."},{"key":"2025030617480293600_r33","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394C(T) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"2025030617480293600_r34","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1182\/blood-2012-11-464685","article-title":"The co-receptor BTLA negatively regulates human V\u03b39V\u03b42 T-cell proliferation: a potential way of immune escape for lymphoma cells","volume":"122","author":"Gertner-Dardenne","year":"2013","journal-title":"Blood"},{"key":"2025030617480293600_r35","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1128\/CVI.00259-09","article-title":"Cryopreservation decreases receptor PD-1 and ligand PD-L1 coinhibitory expression on peripheral blood mononuclear cell-derived T cells and monocytes","volume":"16","author":"Campbell","year":"2009","journal-title":"Clin. Vaccine Immunol."},{"key":"2025030617480293600_r36","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.4049\/jimmunol.1202777","article-title":"Soluble CD80 restores T cell activation and overcomes tumor cell programmed death ligand 1-mediated immune suppression","volume":"191","author":"Haile","year":"2013","journal-title":"J. Immunol."},{"key":"2025030617480293600_r37","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.immuni.2011.06.015","article-title":"Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8+ T cells","volume":"35","author":"Youngblood","year":"2011","journal-title":"Immunity"},{"key":"2025030617480293600_r38","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/ni.2046","article-title":"Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection","volume":"12","author":"Kao","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025030617480293600_r39","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1084\/jem.20130208","article-title":"Blimp-1 represses CD8 T cell expression of PD-1 using a feed-forward transcriptional circuit during acute viral infection","volume":"211","author":"Lu","year":"2014","journal-title":"J. Exp. Med."},{"key":"2025030617480293600_r40","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/icb.2012.53","article-title":"Notch signaling regulates PD-1 expression during CD8+ T-cell activation","volume":"91","author":"Mathieu","year":"2013","journal-title":"Immunol. Cell Biol."},{"key":"2025030617480293600_r41","doi-asserted-by":"crossref","first-page":"4832","DOI":"10.4049\/jimmunol.181.7.4832","article-title":"NFATc1 regulates PD-1 expression upon T cell activation","volume":"181","author":"Oestreich","year":"2008","journal-title":"J. Immunol."},{"key":"2025030617480293600_r42","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.192.Supp.61.6","article-title":"TGF-\u03b21 enhances T-cell PD-1 expression through a Smad3-dependant increase in transcription. (IRM4P.499)","volume":"192","author":"Park","year":"2014","journal-title":"J. Immunol."},{"key":"2025030617480293600_r43","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/nm730","article-title":"Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion","volume":"8","author":"Dong","year":"2002","journal-title":"Nat. Med."},{"key":"2025030617480293600_r44","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/S0014-5793(03)00483-6","article-title":"Microbial isoprenoid biosynthesis and human \u03b3\u03b4 T cell activation","volume":"544","author":"Eberl","year":"2003","journal-title":"FEBS Lett."},{"key":"2025030617480293600_r45","doi-asserted-by":"crossref","first-page":"e72249","DOI":"10.1371\/journal.pone.0072249","article-title":"IFN-\u03b3-stimulated neutrophils suppress lymphocyte proliferation through expression of PD-L1","volume":"8","author":"de Kleijn","year":"2013","journal-title":"PLoS One"},{"key":"2025030617480293600_r46","doi-asserted-by":"crossref","first-page":"26345","DOI":"10.1038\/srep26345","article-title":"Interferon-\u03b3 and tumor necrosis factor-\u03b1 polarize bone marrow stromal cells uniformly to a Th1 phenotype","volume":"6","author":"Jin","year":"2016","journal-title":"Sci. Rep."},{"key":"2025030617480293600_r47","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/srep00295","article-title":"TNF-\u03b1 and TGF-\u03b2 counter-regulate PD-L1 expression on monocytes in systemic lupus erythematosus","volume":"2","author":"Ou","year":"2012","journal-title":"Sci. Rep."},{"key":"2025030617480293600_r48","doi-asserted-by":"crossref","first-page":"8844","DOI":"10.4049\/jimmunol.177.12.8844","article-title":"Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis","volume":"177","author":"Wan","year":"2006","journal-title":"J. Immunol."},{"key":"2025030617480293600_r49","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1093\/infdis\/jit802","article-title":"Cord blood V\u03b32V\u03b42 T cells provide a molecular marker for the influence of pregnancy-associated malaria on neonatal immunity","volume":"209","author":"Cairo","year":"2014","journal-title":"J. Infect. Dis."},{"key":"2025030617480293600_r50","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1093\/infdis\/jiv600","article-title":"Frequent malaria drives progressive V\u03b42 T cell loss, dysfunction, and CD16 upregulation during early childhood","volume":"213","author":"Farrington","year":"2015","journal-title":"J. Infect. Dis."},{"key":"2025030617480293600_r51","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/nm.3568","article-title":"Lung microbiota promotes tolerance to allergens in neonates via PD-L1","volume":"20","author":"Gollwitzer","year":"2014","journal-title":"Nat. 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