{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T18:58:42Z","timestamp":1776279522509,"version":"3.50.1"},"reference-count":40,"publisher":"American Society of Hematology","issue":"26","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,12,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Donor and recipient cytomegalovirus (CMV) serostatus correlate with transplant-related mortality that is associated with reduced survival following allogeneic stem cell transplant (SCT). Prior epidemiologic studies have suggested that CMV seronegative recipients (R\u2013) receiving a CMV-seropositive graft (D+) experience inferior outcomes compared with other serostatus combinations, an observation that appears independent of viral reactivation. We therefore investigated the hypothesis that prior donor CMV exposure irreversibly modifies immunologic function after SCT. We identified a CD4+\/CD57+\/CD27\u2013 T-cell subset that was differentially expressed between D+ and D\u2013 transplants and validated results with 120 patient samples. This T-cell subset represents an average of 2.9% (D\u2013\/R\u2013), 18% (D\u2013\/R+), 12% (D+\/R\u2013), and 19.6% (D+\/R+) (P &amp;lt; .0001) of the total CD4+ T-cell compartment and stably persists for at least several years post-SCT. Even in the absence of CMV reactivation post-SCT, D+\/R\u2013 transplants displayed a significant enrichment of these cells compared with D\u2013\/R\u2013 transplants (P = .0078). These are effector memory cells (CCR7\u2013\/CD45RA+\/\u2212) that express T-bet, Eomesodermin, granzyme B, secrete Th1 cytokines, and are enriched in CMV-specific T cells. These cells are associated with decreased T-cell receptor diversity (P &amp;lt; .0001) and reduced proportions of major histocompatibility class (MHC) II expressing classical monocytes (P &amp;lt; .0001), myeloid (P = .024), and plasmacytoid dendritic cells (P = .0014). These data describe a highly expanded CD4+ T-cell population and putative mechanisms by which prior donor or recipient CMV exposure may create a lasting immunologic imprint following SCT, providing a rationale for using D\u2013 grafts for R\u2013 transplant recipients.<\/jats:p>","DOI":"10.1182\/blood.2020009492","type":"journal-article","created":{"date-parts":[[2021,6,4]],"date-time":"2021-06-04T22:02:03Z","timestamp":1622844123000},"page":"2874-2885","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":23,"title":["CMV exposure drives long-term CD57+ CD4 memory T-cell inflation following allogeneic stem cell transplant"],"prefix":"10.1182","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3455-7360","authenticated-orcid":false,"given":"Albert C.","family":"Yeh","sequence":"first","affiliation":[{"name":"Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;"},{"name":"Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3437-9659","authenticated-orcid":false,"given":"Antiopi","family":"Varelias","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;"},{"name":"Facuty of Medicine, The University of Queensland, Brisbane, QLD, Australia;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anupama","family":"Reddy","sequence":"additional","affiliation":[{"name":"Prism Bioanalytics, Durham, NC;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sierra M.","family":"Barone","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart D.","family":"Olver","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kate","family":"Chilson","sequence":"additional","affiliation":[{"name":"Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynn E.","family":"Onstad","sequence":"additional","affiliation":[{"name":"Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen S.","family":"Ensbey","sequence":"additional","affiliation":[{"name":"Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea S","family":"Henden","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luke","family":"Samson","sequence":"additional","affiliation":[{"name":"Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;"},{"name":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1685-2078","authenticated-orcid":false,"given":"Carla A","family":"Jaeger","sequence":"additional","affiliation":[{"name":"Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5237-7024","authenticated-orcid":false,"given":"Timothy","family":"Bi","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kimberly B.","family":"Dahlman","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tae Kon","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariapia A.","family":"Degli-Esposti","sequence":"additional","affiliation":[{"name":"Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evan W.","family":"Newell","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madan H.","family":"Jagasia","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9428-8866","authenticated-orcid":false,"given":"Jonathan M.","family":"Irish","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2600-6390","authenticated-orcid":false,"given":"Stephanie J.","family":"Lee","sequence":"additional","affiliation":[{"name":"Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;"},{"name":"Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geoffrey R.","family":"Hill","sequence":"additional","affiliation":[{"name":"Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA;"},{"name":"Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"234","reference":[{"issue":"9","key":"2021123016205795700_B1","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/S1083-8791(03)00287-8","article-title":"Cytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies","volume":"9","author":"Boeckh","year":"2003","journal-title":"Biol Blood Marrow Transplant."},{"issue":"1","key":"2021123016205795700_B2","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1182\/asheducation-2011.1.305","article-title":"Complications, diagnosis, management, and prevention of CMV infections: current and future","volume":"2011","author":"Boeckh","year":"2011","journal-title":"Hematology (Am Soc Hematol Educ Program)."},{"issue":"6","key":"2021123016205795700_B3","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1097\/MOH.0000000000000085","article-title":"The role of cytomegalovirus serostatus on outcome of hematopoietic stem cell transplantation","volume":"21","author":"Ljungman","year":"2014","journal-title":"Curr Opin Hematol."},{"issue":"19","key":"2021123016205795700_B4","doi-asserted-by":"crossref","first-page":"3359","DOI":"10.1182\/blood-2013-05-499830","article-title":"CMV serostatus still has an important prognostic impact in de novo acute leukemia patients after allogeneic stem cell transplantation: a report from the Acute Leukemia Working Party of EBMT","volume":"122","author":"Schmidt-Hieber","year":"2013","journal-title":"Blood."},{"issue":"4","key":"2021123016205795700_B5","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1093\/cid\/ciu364","article-title":"Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation","volume":"59","author":"Ljungman","year":"2014","journal-title":"Clin Infect Dis."},{"issue":"3","key":"2021123016205795700_B6","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1086\/338624","article-title":"High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection","volume":"185","author":"Nichols","year":"2002","journal-title":"J Infect Dis."},{"issue":"25","key":"2021123016205795700_B7","doi-asserted-by":"crossref","first-page":"3835","DOI":"10.1182\/blood-2015-03-631853","article-title":"CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCR\u03b2 repertoire","volume":"125","author":"Suessmuth","year":"2015","journal-title":"Blood."},{"issue":"8","key":"2021123016205795700_B8","first-page":"e318","article-title":"Characterization of CMV-specific CD4+ T-cell reconstitution following stem cell transplantation through the use of HLA Class II- peptide tetramers identifies patients at high risk of recurrent CMV reactivation","volume":"100","author":"Raeiszadeh","year":"2015","journal-title":"Haematologica."},{"key":"2021123016205795700_B9","article-title":"Dimensionality reduction for visualizing single-cell data using UMAP [published online ahead of print 3 December 2018]","author":"Becht","journal-title":"Nat Biotechnol."},{"issue":"1","key":"2021123016205795700_B10","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.cell.2015.05.047","article-title":"Data-driven phenotypic dissection of AML reveals progenitor-like cells that correlate with prognosis","volume":"162","author":"Levine","year":"2015","journal-title":"Cell."},{"issue":"3","key":"2021123016205795700_B11","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/nmeth.4149","article-title":"Characterizing cell subsets using marker enrichment modeling","volume":"14","author":"Diggins","year":"2017","journal-title":"Nat Methods."},{"issue":"4","key":"2021123016205795700_B12","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1182\/blood-2007-04-079863","article-title":"CD4+ T cells specific for glycoprotein B from cytomegalovirus exhibit extreme conservation of T-cell receptor usage between different individuals","volume":"111","author":"Crompton","year":"2008","journal-title":"Blood."},{"issue":"5","key":"2021123016205795700_B13","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1084\/jem.20121437","article-title":"MHC II tetramers visualize human CD4+ T cell responses to Epstein-Barr virus infection and demonstrate atypical kinetics of the nuclear antigen EBNA1 response","volume":"210","author":"Long","year":"2013","journal-title":"J Exp Med."},{"issue":"5","key":"2021123016205795700_B14","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.humimm.2004.02.019","article-title":"MHC class II tetramers containing influenza hemagglutinin and EBV EBNA1 epitopes detect reliably specific CD4(+) T cells in healthy volunteers","volume":"65","author":"Ye","year":"2004","journal-title":"Hum Immunol."},{"issue":"2","key":"2021123016205795700_B15","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1006\/viro.1995.0076","article-title":"Isolation of cytotoxic T lymphocytes from healthy seropositive individuals specific for peptide epitopes from Epstein-Barr virus nuclear antigen 1: implications for viral persistence and tumor surveillance","volume":"214","author":"Khanna","year":"1995","journal-title":"Virology."},{"issue":"6","key":"2021123016205795700_B16","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/nmeth.2960","article-title":"Towards error-free profiling of immune repertoires","volume":"11","author":"Shugay","year":"2014","journal-title":"Nat Methods."},{"issue":"11","key":"2021123016205795700_B17","doi-asserted-by":"crossref","first-page":"e1004503","DOI":"10.1371\/journal.pcbi.1004503","article-title":"VDJtools: unifying post-analysis of T cell receptor repertoires","volume":"11","author":"Shugay","year":"2015","journal-title":"PLOS Comput Biol."},{"issue":"4148","key":"2021123016205795700_B18","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/163688a0","article-title":"Measurement of diversity","volume":"163","author":"Simpson","year":"1949","journal-title":"Nature."},{"issue":"2","key":"2021123016205795700_B19","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1189\/jlb.4A0316-112R","article-title":"CMV induces expansion of highly polyfunctional CD4+ T cell subset coexpressing CD57 and CD154","volume":"101","author":"Pera","year":"2017","journal-title":"J Leukoc Biol."},{"issue":"5647","key":"2021123016205795700_B20","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1126\/science.1090148","article-title":"Control of effector CD8+ T cell function by the transcription factor Eomesodermin","volume":"302","author":"Pearce","year":"2003","journal-title":"Science."},{"issue":"1-2","key":"2021123016205795700_B21","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.imlet.2012.02.013","article-title":"Ectopic expression of a T-box transcription factor, eomesodermin, renders CD4(+) Th cells cytotoxic by activating both perforin- and FasL-pathways","volume":"144","author":"Eshima","year":"2012","journal-title":"Immunol Lett."},{"key":"2021123016205795700_B22","doi-asserted-by":"crossref","first-page":"S196","DOI":"10.1093\/cid\/cit587","article-title":"Cytomegalovirus vaccines","volume":"57","author":"McVoy","year":"2013","journal-title":"Clin Infect Dis."},{"issue":"12","key":"2021123016205795700_B23","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1586\/erv.10.132","article-title":"Cytolytic CD4(+) T cells in viral immunity","volume":"9","author":"Soghoian","year":"2010","journal-title":"Expert Rev Vaccines."},{"issue":"13","key":"2021123016205795700_B24","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.1084\/jem.20052246","article-title":"Acquisition of direct antiviral effector functions by CMV-specific CD4+ T lymphocytes with cellular maturation","volume":"203","author":"Casazza","year":"2006","journal-title":"J Exp Med."},{"issue":"8","key":"2021123016205795700_B25","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1111\/j.1365-2893.2006.00723.x","article-title":"Cytotoxic CD4 T cells in viral hepatitis","volume":"13","author":"Aslan","year":"2006","journal-title":"J Viral Hepat."},{"issue":"4","key":"2021123016205795700_B26","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.4049\/jimmunol.169.4.2172","article-title":"Inhibition of EBV-induced lymphoproliferation by CD4(+) T cells specific for an MHC class II promiscuous epitope","volume":"169","author":"Omiya","year":"2002","journal-title":"J Immunol."},{"issue":"7","key":"2021123016205795700_B27","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1097\/QAD.0b013e328337b144","article-title":"Cytotoxic granule release dominates gag-specific CD4+ T-cell response in different phases of HIV infection","volume":"24","author":"Nemes","year":"2010","journal-title":"AIDS."},{"issue":"6","key":"2021123016205795700_B28","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1182\/blood-2003-10-3616","article-title":"The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy","volume":"103","author":"Boeckh","year":"2004","journal-title":"Blood."},{"issue":"1","key":"2021123016205795700_B29","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1146\/annurev-immunol-042617-053206","article-title":"Rebooting human immunology","volume":"36","author":"Davis","year":"2018","journal-title":"Annu Rev Immunol."},{"issue":"12","key":"2021123016205795700_B30","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1182\/blood-2015-01-622837","article-title":"Acute GVHD results in a severe DC defect that prevents T-cell priming and leads to fulminant cytomegalovirus disease in mice","volume":"126","author":"Wikstrom","year":"2015","journal-title":"Blood."},{"issue":"2","key":"2021123016205795700_B31","doi-asserted-by":"crossref","first-page":"614","DOI":"10.4049\/jimmunol.174.2.614","article-title":"Cutting edge: MHC class II-restricted killing in vivo during viral infection","volume":"174","author":"Jellison","year":"2005","journal-title":"J Immunol."},{"issue":"4","key":"2021123016205795700_B32","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.coi.2009.05.012","article-title":"Biomarkers of human immunosenescence: impact of Cytomegalovirus infection","volume":"21","author":"Derhovanessian","year":"2009","journal-title":"Curr Opin Immunol."},{"issue":"13","key":"2021123016205795700_B33","doi-asserted-by":"crossref","first-page":"4543","DOI":"10.1182\/blood-2007-05-092130","article-title":"Delayed immune reconstitution after cord blood transplantation is characterized by\u00a0impaired thymopoiesis and late memory\u00a0T-cell skewing","volume":"110","author":"Komanduri","year":"2007","journal-title":"Blood."},{"issue":"10","key":"2021123016205795700_B34","doi-asserted-by":"crossref","first-page":"6167","DOI":"10.4049\/jimmunol.0902068","article-title":"Human late memory CD8+ T cells have a distinct cytokine signature characterized by CC chemokine production without IL-2 production","volume":"183","author":"Kim","year":"2009","journal-title":"J Immunol."},{"issue":"23","key":"2021123016205795700_B35","doi-asserted-by":"crossref","first-page":"4617","DOI":"10.1182\/blood-2012-12-476218","article-title":"MEK inhibitors selectively suppress alloreactivity and graft-versus-host disease in a memory stage-dependent manner","volume":"121","author":"Shindo","year":"2013","journal-title":"Blood."},{"issue":"7","key":"2021123016205795700_B36","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1182\/blood-2002-07-2103","article-title":"Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells","volume":"101","author":"Brenchley","year":"2003","journal-title":"Blood."},{"issue":"3","key":"2021123016205795700_B37","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1182\/blood-2016-04-713644","article-title":"Cytomegalovirus replication reduces the relapse incidence in patients with acute myeloid leukemia","volume":"128","author":"Elmaagacli","year":"2016","journal-title":"Blood."},{"issue":"5","key":"2021123016205795700_B38","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1182\/blood-2010-08-304121","article-title":"Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients","volume":"118","author":"Elmaagacli","year":"2011","journal-title":"Blood."},{"issue":"3","key":"2021123016205795700_B39","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.chom.2014.02.002","article-title":"Cytomegalovirus hijacks CX3CR1(hi) patrolling monocytes as immune-privileged vehicles for dissemination in mice","volume":"15","author":"Daley-Bauer","year":"2014","journal-title":"Cell Host Microbe."},{"issue":"20","key":"2021123016205795700_B40","doi-asserted-by":"crossref","first-page":"11137","DOI":"10.1073\/pnas.93.20.11137","article-title":"Human cytomegalovirus latent gene expression in\u00a0granulocyte-macrophage progenitors in\u00a0culture and in seropositive individuals","volume":"93","author":"Kondo","year":"1996","journal-title":"Proc Natl Acad Sci USA."}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/138\/26\/2874\/1856046\/bloodbld2020009492.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/138\/26\/2874\/1856046\/bloodbld2020009492.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,30]],"date-time":"2021-12-30T16:22:48Z","timestamp":1640881368000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/138\/26\/2874\/476063\/CMV-exposure-drives-long-term-CD57-CD4-memory-T"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,30]]},"references-count":40,"journal-issue":{"issue":"26","published-print":{"date-parts":[[2021,12,30]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2020009492","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,30]]}}}