{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T21:52:04Z","timestamp":1775944324840,"version":"3.50.1"},"reference-count":54,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2015,4,16]],"date-time":"2015-04-16T00:00:00Z","timestamp":1429142400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0124246","type":"journal-article","created":{"date-parts":[[2015,4,16]],"date-time":"2015-04-16T19:06:25Z","timestamp":1429211185000},"page":"e0124246","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":20,"title":["Lymphocyte Gene Expression Signatures from Patients and Mouse Models of Hereditary Hemochromatosis Reveal a Function of HFE as a Negative Regulator of CD8+ T-Lymphocyte Activation and Differentiation In Vivo"],"prefix":"10.1371","volume":"10","author":[{"given":"M\u00f3nica","family":"Costa","sequence":"first","affiliation":[]},{"given":"Eug\u00e9nia","family":"Cruz","sequence":"additional","affiliation":[]},{"given":"Susana","family":"Oliveira","sequence":"additional","affiliation":[]},{"given":"Vladimir","family":"Benes","sequence":"additional","affiliation":[]},{"given":"Tomi","family":"Ivacevic","sequence":"additional","affiliation":[]},{"given":"Maria Jo\u00e3o","family":"Silva","sequence":"additional","affiliation":[]},{"given":"In\u00eas","family":"Vieira","sequence":"additional","affiliation":[]},{"given":"Francisco","family":"Dias","sequence":"additional","affiliation":[]},{"given":"S\u00f3nia","family":"Fonseca","sequence":"additional","affiliation":[]},{"given":"Marta","family":"Gon\u00e7alves","sequence":"additional","affiliation":[]},{"given":"Margarida","family":"Lima","sequence":"additional","affiliation":[]},{"given":"Catarina","family":"Leit\u00e3o","sequence":"additional","affiliation":[]},{"given":"Martina U.","family":"Muckenthaler","sequence":"additional","affiliation":[]},{"given":"Jorge","family":"Pinto","sequence":"additional","affiliation":[]},{"given":"Gra\u00e7a","family":"Porto","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2015,4,16]]},"reference":[{"key":"ref1","first-page":"89","article-title":"A study of 609 HLA haplotypes marking for the hemochromatosis gene: (1) mapping of the gene near the HLA-A locus and characters required to define a heterozygous population and (2) hypothesis concerning the underlying cause of hemochromatosis-HLA association","volume":"41","author":"M Simon","year":"1987","journal-title":"Am J Hum Genet"},{"key":"ref2","first-page":"51","article-title":"Hemochromatosis Genetics, Pathophysiology, Diagnosis, and Treatment","author":"G SM Porto","year":"2000"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/ng0896-399","article-title":"A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis","volume":"13","author":"JN Feder","year":"1996","journal-title":"Nat Genet"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/j.jhep.2012.06.015","article-title":"The hemochromatosis proteins HFE, TfR2, and HJV form a membrane-associated protein complex for hepcidin regulation","volume":"57","author":"F D'Alessio","year":"2012","journal-title":"J Hepatol"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"4707","DOI":"10.3748\/wjg.v13.i35.4707","article-title":"Iron overload and immunity","volume":"13","author":"G Porto","year":"2007","journal-title":"World J Gastroenterol"},{"key":"ref6","first-page":"481","article-title":"Stability of CD4\/CD8 ratios in man: new correlation between CD4\/CD8 profiles and iron overload in idiopathic haemochromatosis patients","volume":"313","author":"R Reimao","year":"1991","journal-title":"C R Acad Sci III"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/j.1600-0609.1994.tb00097.x","article-title":"Haemochromatosis as a window into the study of the immunological system: a novel correlation between CD8+ lymphocytes and iron overload","volume":"52","author":"G Porto","year":"1994","journal-title":"Eur J Haematol"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.bcmd.2006.04.004","article-title":"The CD8+ T-lymphocyte profile as a modifier of iron overload in HFE hemochromatosis: an update of clinical and immunological data from 70 C282Y homozygous subjects","volume":"37","author":"E Cruz","year":"2006","journal-title":"Blood Cells Mol Dis"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1046\/j.1365-2362.2001.00744.x","article-title":"Hepatic damage in C282Y homozygotes relates to low numbers of CD8+ cells in the liver lobuli","volume":"31","author":"EM Cardoso","year":"2001","journal-title":"Eur J Clin Invest"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1111\/j.1365-2249.2009.04066.x","article-title":"Low numbers of CD8+ T lymphocytes in hereditary haemochromatosis are explained by a decrease of the most mature CD8+ effector memory T cells","volume":"159","author":"MF Macedo","year":"2010","journal-title":"Clin Exp Immunol"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1111\/j.1365-3083.1994.tb03396.x","article-title":"Decreased CD8-p56lck activity in peripheral blood T-lymphocytes from patients with hereditary haemochromatosis","volume":"39","author":"FA Arosa","year":"1994","journal-title":"Scand J Immunol"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1046\/j.1365-2249.1997.d01-967.x","article-title":"Anomalies of the CD8+ T cell pool in haemochromatosis: HLA-A3-linked expansions of CD8+CD28- T cells","volume":"107","author":"FA Arosa","year":"1997","journal-title":"Clin Exp Immunol"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/S0168-8278(02)00276-3","article-title":"Peripheral lymphocytes and intracellular cytokines in C282Y homozygous hemochromatosis patients","volume":"37","author":"G Fabio","year":"2002","journal-title":"J Hepatol"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1002\/eji.201343955","article-title":"The WT hemochromatosis protein HFE inhibits CD8(+) T-lymphocyte activation","volume":"44","author":"A Reuben","year":"2014","journal-title":"Eur J Immunol"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1084\/jem.20062349","article-title":"CD8 single-cell gene coexpression reveals three different effector types present at distinct phases of the immune response","volume":"204","author":"A Peixoto","year":"2007","journal-title":"J Exp Med"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/1471-2350-9-97","article-title":"A new 500 kb haplotype associated with high CD8+ T-lymphocyte numbers predicts a less severe expression of hereditary hemochromatosis","volume":"9","author":"E Cruz","year":"2008","journal-title":"BMC Med Genet"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1471-2350-7-16","article-title":"A study of 82 extended HLA haplotypes in HFE-C282Y homozygous hemochromatosis subjects: relationship to the genetic control of CD8+ T-lymphocyte numbers and severity of iron overload","volume":"7","author":"E Cruz","year":"2006","journal-title":"BMC Med Genet"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"e79990","DOI":"10.1371\/journal.pone.0079990","article-title":"Effects of highly conserved major histocompatibility complex (MHC) extended haplotypes on iron and low CD8+ T lymphocyte phenotypes in HFE C282Y homozygous hemochromatosis patients from three geographically distant areas","volume":"8","author":"M Costa","year":"2013","journal-title":"PLoS One"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1002\/eji.200939722","article-title":"Heterogeneity of CD4+ memory T cells: functional modules for tailored immunity","volume":"39","author":"F Sallusto","year":"2009","journal-title":"Eur J Immunol"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.1182\/blood-2006-06-027060","article-title":"Cartography of gene expression in CD8 single cells: novel CCR7- subsets suggest differentiation independent of CD45RA expression","volume":"109","author":"M Monteiro","year":"2007","journal-title":"Blood"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.4049\/jimmunol.176.3.1439","article-title":"Human naive CD8 T cells down-regulate expression of the WNT pathway transcription factors lymphoid enhancer binding factor 1 and transcription factor 7 (T cell factor-1) following antigen encounter in vitro and in vivo","volume":"176","author":"T Willinger","year":"2006","journal-title":"J Immunol"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/imr.12123","article-title":"Coordinate control of cytoskeletal remodeling and calcium mobilization during T-cell activation","volume":"256","author":"A Babich","year":"2013","journal-title":"Immunol Rev"},{"key":"ref23","first-page":"1367","article-title":"Expression and function of FRA2\/JUND in cutaneous T-cell lymphomas","volume":"32","author":"T Nakayama","year":"2012","journal-title":"Anticancer Res"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0167-4781(00)00094-4","article-title":"Expression of purinergic receptors (ionotropic P2X1-7 and metabotropic P2Y1-11) during myeloid differentiation of HL60 cells","volume":"1492","author":"K Adrian","year":"2000","journal-title":"Biochim Biophys Acta"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"3569","DOI":"10.1128\/MCB.01909-08","article-title":"Knockdown of human N alpha-terminal acetyltransferase complex C leads to p53-dependent apoptosis and aberrant human Arl8b localization","volume":"29","author":"KK Starheim","year":"2009","journal-title":"Mol Cell Biol"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1756-8935-4-15","article-title":"Histone H1 interphase phosphorylation becomes largely established in G1 or early S phase and differs in G1 between T-lymphoblastoid cells and normal T cells","volume":"4","author":"A Green","year":"2011","journal-title":"Epigenetics Chromatin"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"e69395","DOI":"10.1371\/journal.pone.0069395","article-title":"S100A8\/A9 (calprotectin) negatively regulates G2\/M cell cycle progression and growth of squamous cell carcinoma","volume":"8","author":"A Khammanivong","year":"2013","journal-title":"PLoS One"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/nm.2150","article-title":"The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells","volume":"16","author":"K Loser","year":"2010","journal-title":"Nat Med"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1182\/blood-2004-01-0150","article-title":"Self-reactive memory-phenotype CD8 T cells exhibit both MHC-restricted and non-MHC-restricted cytotoxicity: a role for the T-cell receptor and natural killer cell receptors","volume":"104","author":"S Dhanji","year":"2004","journal-title":"Blood"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1016\/S0888-7543(03)00070-3","article-title":"Identification of RELMgamma, a novel resistin-like molecule with a distinct expression pattern","volume":"81","author":"B Gerstmayer","year":"2003","journal-title":"Genomics"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.it.2004.08.008","article-title":"Signal regulators in FcR-mediated activation of leukocytes?","volume":"25","author":"P Mina-Osorio","year":"2004","journal-title":"Trends Immunol"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"9229","DOI":"10.1073\/pnas.1318731111","article-title":"Human memory T cells from the bone marrow are resting and maintain long-lasting systemic memory","volume":"111","author":"A Okhrimenko","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"2961","DOI":"10.4049\/jimmunol.1400003","article-title":"Cutting edge: resident memory CD8 T cells occupy frontline niches in secondary lymphoid organs","volume":"192","author":"JM Schenkel","year":"2014","journal-title":"J Immunol"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"3346","DOI":"10.1002\/eji.201142351","article-title":"Lipocalin-2 ameliorates granulocyte functionality","volume":"42","author":"A Schroll","year":"2012","journal-title":"Eur J Immunol"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/j.1365-3083.2011.02613.x","article-title":"Rough-Form-Lipopolysaccharide Increase Apoptosis in Human CD4(+) and CD8(+) T-Lymphocytes","volume":"75","author":"JS Nielsen","year":"2011","journal-title":"Scand J Immunol"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"581","DOI":"10.3349\/ymj.2011.52.4.581","article-title":"Apoptosis of T lymphocytes isolated from peripheral blood of patients with acute exacerbation of chronic obstructive pulmonary disease","volume":"52","author":"SC Lim","year":"2011","journal-title":"Yonsei Med J"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1002\/jcp.21009","article-title":"Ferritin-a mediator of apoptosis?","volume":"212","author":"N Bresgen","year":"2007","journal-title":"J Cell Physiol"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3109\/01913123.2011.630125","article-title":"Iron-induced damage in corpus striatal cells of neonatal rats: attenuation by folic acid","volume":"36","author":"HM Saadeldien","year":"2012","journal-title":"Ultrastruct Pathol"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.mrgentox.2008.11.016","article-title":"Increased capacity of lymphocytes from hereditary hemochromatosis patients homozygous for the C282Y HFE mutation to respond to the genotoxic effect of diepoxybutane","volume":"673","author":"B Porto","year":"2009","journal-title":"Mutat Res"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1186\/1471-2164-8-379","article-title":"Effects of iron loading on muscle: genome-wide mRNA expression profiling in the mouse","volume":"8","author":"A Rodriguez","year":"2007","journal-title":"BMC Genomics"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1002\/hep.510250223","article-title":"Relative impact of HLA phenotype and CD4-CD8 ratios on the clinical expression of hemochromatosis","volume":"25","author":"G Porto","year":"1997","journal-title":"Hepatology"},{"key":"ref42","first-page":"497","article-title":"Suggested models of ecotaxopathy in lymphoreticular malignancy. A role for iron-binding proteins in the control of lymphoid cell migration","volume":"90","author":"M de Sousa","year":"1978","journal-title":"Am J Pathol"},{"key":"ref43","doi-asserted-by":"crossref","unstructured":"de Sousa M, Reimao R, Porto G, Grady RW, Hilgartner MW, Giardina P. Iron and lymphocytes: reciprocal regulatory interactions. Curr Stud Hematol Blood Transfus. 1991; 171\u2013177.","DOI":"10.1159\/000419357"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0165-2478(94)90094-9","article-title":"Iron overload in beta 2-microglobulin-deficient mice","volume":"39","author":"M de Sousa","year":"1994","journal-title":"Immunol Lett"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1111\/j.1749-6632.1988.tb55515.x","article-title":"Iron, iron-binding proteins and immune system cells","volume":"526","author":"M De Sousa","year":"1988","journal-title":"Ann N Y Acad Sci"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"4239","DOI":"10.1182\/blood-2002-05-1565","article-title":"Increased hepatic iron in mice lacking classical MHC class I molecules","volume":"100","author":"EM Cardoso","year":"2002","journal-title":"Blood"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"e79870","DOI":"10.1371\/journal.pone.0079870","article-title":"Non-transferrin-bound iron (NTBI) uptake by T lymphocytes: evidence for the selective acquisition of oligomeric ferric citrate species","volume":"8","author":"J Arezes","year":"2013","journal-title":"PLoS One"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fphar.2014.00024","article-title":"Physiological implications of NTBI uptake by T lymphocytes","volume":"5","author":"JP Pinto","year":"2014","journal-title":"Front Pharmacol"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/nri1635","article-title":"MHC class Ib molecules bridge innate and acquired immunity","volume":"5","author":"JR Rodgers","year":"2005","journal-title":"Nat Rev Immunol"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"e45478","DOI":"10.1371\/journal.pone.0045478","article-title":"An inflammation loop orchestrated by S100A9 and calprotectin is critical for development of arthritis","volume":"7","author":"A Cesaro","year":"2012","journal-title":"PLoS One"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"13312","DOI":"10.1073\/pnas.96.23.13312","article-title":"Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism","volume":"96","author":"S Bahram","year":"1999","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1172\/JCI102639","article-title":"Iron metabolism; iron stores in man as measured by phlebotomy","volume":"31","author":"D Haskins","year":"1952","journal-title":"J Clin Invest"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1101\/gr.2890204","article-title":"Quantification of multiple gene expression in individual cells","volume":"14","author":"A Peixoto","year":"2004","journal-title":"Genome Res"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1006\/bcmd.2000.0342","article-title":"Immunophenotypic aberrations, DNA content, and cell cycle analysis of plasma cells in patients with myeloma and monoclonal gammopathies","volume":"26","author":"M Lima","year":"2000","journal-title":"Blood Cells Mol Dis"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0124246","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T00:01:59Z","timestamp":1598918519000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0124246"}},"subtitle":[],"editor":[{"given":"Kostas","family":"Pantopoulos","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2015,4,16]]},"references-count":54,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2015,4,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0124246","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,4,16]]}}}