{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T10:21:40Z","timestamp":1793701300585,"version":"4.5.1"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2018,5,1]],"date-time":"2018-05-01T00:00:00Z","timestamp":1525132800000},"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":[[2018,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In the context of infectious diseases, cell population transcriptomics are useful to gain mechanistic insight into protective immune responses, which is not possible using traditional whole-blood approaches. In this study, we applied a cell population transcriptomics strategy to sorted memory CD4 T cells to define novel immune signatures of latent tuberculosis infection (LTBI) and gain insight into the phenotype of tuberculosis (TB)-specific CD4 T cells. We found a 74-gene signature that could discriminate between memory CD4 T cells from healthy latently Mycobacterium tuberculosis\u2013infected subjects and noninfected controls. The gene signature presented a significant overlap with the gene signature of the Th1* (CCR6+CXCR3+CCR4\u2212) subset of CD4 T cells, which contains the majority of TB-specific reactivity and is expanded in LTBI. In particular, three Th1* genes (ABCB1, c-KIT, and GPA33) were differentially expressed at the RNA and protein levels in memory CD4 T cells of LTBI subjects compared with controls. The 74-gene signature also highlighted novel phenotypic markers that further defined the CD4 T cell subset containing TB specificity. We found the majority of TB-specific epitope reactivity in the CD62L\u2212GPA33\u2212 Th1* subset. Thus, by combining cell population transcriptomics and single-cell protein-profiling techniques, we identified a CD4 T cell immune signature of LTBI that provided novel insights into the phenotype of TB-specific CD4 T cells.<\/jats:p>","DOI":"10.4049\/jimmunol.1800118","type":"journal-article","created":{"date-parts":[[2018,3,30]],"date-time":"2018-03-30T09:55:14Z","timestamp":1522403714000},"page":"3283-3290","source":"Crossref","is-referenced-by-count":48,"title":["Transcriptomic Analysis of CD4+ T Cells Reveals Novel Immune Signatures of Latent Tuberculosis"],"prefix":"10.1093","volume":"200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1692-2758","authenticated-orcid":false,"given":"Julie G","family":"Burel","sequence":"first","affiliation":[{"name":"Department of Vaccine Discovery, La Jolla Institute for Allergy and Immunology , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia S","family":"Lindestam Arlehamn","sequence":"additional","affiliation":[{"name":"Department of Vaccine Discovery, La Jolla Institute for Allergy and Immunology , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3090-3772","authenticated-orcid":false,"given":"Nabeela","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Vaccine Discovery, La Jolla Institute for Allergy and Immunology , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8164-6852","authenticated-orcid":false,"given":"Gr\u00e9gory","family":"Seumois","sequence":"additional","affiliation":[{"name":"Department of Vaccine Discovery, La Jolla Institute for Allergy and Immunology , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1381-0390","authenticated-orcid":false,"given":"Jason A","family":"Greenbaum","sequence":"additional","affiliation":[{"name":"Department of Vaccine Discovery, La Jolla Institute for Allergy and Immunology , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0109-5991","authenticated-orcid":false,"given":"Randy","family":"Taplitz","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of California , San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H","family":"Gilman","sequence":"additional","affiliation":[{"name":"Johns Hopkins University Bloomberg School of Public Health , Baltimore, MD 21205"},{"name":"Universidad Peruana Caytano Hereida , Lima 15102,","place":["Peru"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4622-7027","authenticated-orcid":false,"given":"Mayuko","family":"Saito","sequence":"additional","affiliation":[{"name":"Johns Hopkins University Bloomberg School of Public Health , Baltimore, MD 21205"},{"name":"Universidad Peruana Caytano Hereida , Lima 15102,","place":["Peru"]},{"name":"Department of Virology, Tohoku University Graduate School of Medicine , Sendai 9808575,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pandurangan","family":"Vijayanand","sequence":"additional","affiliation":[{"name":"Department of Vaccine Discovery, La Jolla Institute for Allergy and Immunology , La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7013-2250","authenticated-orcid":false,"given":"Alessandro","family":"Sette","sequence":"additional","affiliation":[{"name":"Department of Vaccine Discovery, La Jolla Institute for Allergy and Immunology , La Jolla, CA 92037"},{"name":"Department of Medicine, University of California , San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8457-6693","authenticated-orcid":false,"given":"Bjoern","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of Vaccine Discovery, La Jolla Institute for Allergy and Immunology , La Jolla, CA 92037"},{"name":"Department of Medicine, University of California , San Diego, La Jolla, CA 92093"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,5,1]]},"reference":[{"key":"2025030610145589700_r1","author":"World Health Organization","year":"2017"},{"key":"2025030610145589700_r2","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1038\/nature09247","article-title":"An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis","volume":"466","author":"Berry","year":"2010","journal-title":"Nature"},{"key":"2025030610145589700_r3","doi-asserted-by":"crossref","first-page":"e1001538","DOI":"10.1371\/journal.pmed.1001538","article-title":"Detection of tuberculosis in HIV-infected and -uninfected African adults using whole blood RNA expression signatures: a case-control study","volume":"10","author":"Kaforou","year":"2013","journal-title":"PLoS Med."},{"key":"2025030610145589700_r4","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1056\/NEJMoa1303657","article-title":"Diagnosis of childhood tuberculosis and host RNA expression in Africa","volume":"370","author":"Anderson","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"2025030610145589700_r5","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S2213-2600(16)00048-5","article-title":"Genome-wide expression for diagnosis of pulmonary tuberculosis: a multicohort analysis","volume":"4","author":"Sweeney","year":"2016","journal-title":"Lancet Respir. Med."},{"key":"2025030610145589700_r6","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1183\/13993003.02121-2015","article-title":"A 380-gene meta-signature of active tuberculosis compared with healthy controls","volume":"47","author":"Blankley","year":"2016","journal-title":"Eur. Respir. J."},{"key":"2025030610145589700_r7","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1172\/JCI31097","article-title":"Neutrophil-mediated innate immune resistance to mycobacteria","volume":"117","author":"Martineau","year":"2007","journal-title":"J. Clin. Invest."},{"key":"2025030610145589700_r8","doi-asserted-by":"crossref","first-page":"e0171358","DOI":"10.1371\/journal.pone.0171358","article-title":"Quantitative and qualitative profiles of circulating monocytes may help identifying tuberculosis infection and disease stages","volume":"12","author":"La Manna","year":"2017","journal-title":"PLoS One"},{"key":"2025030610145589700_r9","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.1016\/S0140-6736(15)01316-1","article-title":"A blood RNA signature for tuberculosis disease risk: a prospective cohort study","volume":"387","author":"Zak","year":"2016","journal-title":"Lancet"},{"key":"2025030610145589700_r10","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1136\/ard.2009.108043","article-title":"Novel expression signatures identified by transcriptional analysis of separated leucocyte subsets in systemic lupus erythematosus and vasculitis","volume":"69","author":"Lyons","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"2025030610145589700_r11","doi-asserted-by":"crossref","first-page":"4170","DOI":"10.1172\/JCI59255","article-title":"Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis","volume":"121","author":"Lee","year":"2011","journal-title":"J. Clin. Invest."},{"key":"2025030610145589700_r12","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1128\/JVI.01846-10","article-title":"Transcriptional profiling of CD4 T cells identifies distinct subgroups of HIV-1 elite controllers","volume":"85","author":"Vigneault","year":"2011","journal-title":"J. Virol."},{"key":"2025030610145589700_r13","doi-asserted-by":"crossref","first-page":"655","DOI":"10.4049\/jimmunol.1600397","article-title":"Transcriptional profiling of Th2 cells identifies pathogenic features associated with asthma","volume":"197","author":"Seumois","year":"2016","journal-title":"J. Immunol."},{"key":"2025030610145589700_r14","doi-asserted-by":"crossref","first-page":"250ra114","DOI":"10.1126\/scitranslmed.3009546","article-title":"IL-32 is a molecular marker of a host defense network in human tuberculosis","volume":"6","author":"Montoya","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"2025030610145589700_r15","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1056\/NEJM199106063242307","article-title":"Tuberculosis in patients with human immunodeficiency virus infection","volume":"324","author":"Barnes","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"2025030610145589700_r16","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1146\/annurev.immunol.19.1.93","article-title":"Immunology of tuberculosis","volume":"19","author":"Flynn","year":"2001","journal-title":"Annu. Rev. Immunol."},{"key":"2025030610145589700_r17","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1002\/eji.201040455","article-title":"Multifunctional CD4(+) T cells correlate with active Mycobacterium tuberculosis infection","volume":"40","author":"Caccamo","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"2025030610145589700_r18","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/srep00216","article-title":"Multifunctional CD4 T cell responses in patients with active tuberculosis","volume":"2","author":"Qiu","year":"2012","journal-title":"Sci. Rep."},{"key":"2025030610145589700_r19","doi-asserted-by":"crossref","first-page":"11290","DOI":"10.1038\/ncomms11290","article-title":"T-cell activation is an immune correlate of risk in BCG vaccinated infants","volume":"7","author":"Fletcher","year":"2016","journal-title":"Nat. Commun."},{"key":"2025030610145589700_r20","doi-asserted-by":"crossref","first-page":"5298","DOI":"10.1016\/j.vaccine.2016.09.002","article-title":"Polyfunctional CD4 T-cells correlate with in vitro mycobacterial growth inhibition following Mycobacterium bovis BCG-vaccination of infants","volume":"34","author":"Smith","year":"2016","journal-title":"Vaccine"},{"key":"2025030610145589700_r21","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/gene.2010.51","article-title":"Human gene expression profiles of susceptibility and resistance in tuberculosis","volume":"12","author":"Maertzdorf","year":"2011","journal-title":"Genes Immun."},{"key":"2025030610145589700_r22","doi-asserted-by":"crossref","first-page":"e1005760","DOI":"10.1371\/journal.ppat.1005760","article-title":"A quantitative analysis of complexity of human pathogen-specific CD4 T cell responses in healthy M. tuberculosis infected South Africans","volume":"12","author":"Lindestam Arlehamn","year":"2016","journal-title":"PLoS Pathog."},{"key":"2025030610145589700_r23","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1084\/jem.20130301","article-title":"Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids","volume":"211","author":"Ramesh","year":"2014","journal-title":"J. Exp. Med."},{"key":"2025030610145589700_r24","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1038\/s41467-017-01728-5","article-title":"Unique phenotypes and clonal expansions of human CD4 effector memory T cells re-expressing CD45RA","volume":"8","author":"Tian","year":"2017","journal-title":"Nat. Commun."},{"key":"2025030610145589700_r25","first-page":"70","article-title":"An integrated nano-scale approach to profile miRNAs in limited clinical samples","volume":"1","author":"Seumois","year":"2012","journal-title":"Am. J. Clin. Exp. Immunol."},{"key":"2025030610145589700_r26","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/nprot.2014.006","article-title":"Full-length RNA-seq from single cells using Smart-seq2","volume":"9","author":"Picelli","year":"2014","journal-title":"Nat. Protoc."},{"key":"2025030610145589700_r27","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1093\/bioinformatics\/btp120","article-title":"TopHat: discovering splice junctions with RNA-Seq","volume":"25","author":"Trapnell","year":"2009","journal-title":"Bioinformatics"},{"key":"2025030610145589700_r28","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1093\/bioinformatics\/btr026","article-title":"Quality control and preprocessing of metagenomic datasets","volume":"27","author":"Schmieder","year":"2011","journal-title":"Bioinformatics"},{"key":"2025030610145589700_r29","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The sequence alignment\/map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2025030610145589700_r30","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq--a Python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"2025030610145589700_r31","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"2025030610145589700_r32","doi-asserted-by":"crossref","first-page":"a029421","DOI":"10.1101\/cshperspect.a029421","article-title":"Do memory CD4 T cells keep their cell-type programming: plasticity versus fate commitment? T-cell heterogeneity, plasticity, and selection in humans","volume":"10","author":"Sallusto","year":"2018","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"2025030610145589700_r33","doi-asserted-by":"crossref","first-page":"e1003130","DOI":"10.1371\/journal.ppat.1003130","article-title":"Memory T cells in latent Mycobacterium tuberculosis infection are directed against three antigenic islands and largely contained in a CXCR3+CCR6+ Th1 subset","volume":"9","author":"Lindestam Arlehamn","year":"2013","journal-title":"PLoS Pathog."},{"key":"2025030610145589700_r34","doi-asserted-by":"crossref","first-page":"2931","DOI":"10.4049\/jimmunol.1401151","article-title":"Transcriptional profile of tuberculosis antigen-specific T cells reveals novel multifunctional features","volume":"193","author":"Arlehamn","year":"2014","journal-title":"J. Immunol."},{"key":"2025030610145589700_r35","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700849","article-title":"Characterization of Mycobacterium tuberculosis-specific cells using MHC class II tetramers reveals phenotypic differences related to HIV infection and tuberculosis disease","volume-title":"J. Immunol.","author":"Strickland","year":"2017"},{"key":"2025030610145589700_r36","doi-asserted-by":"crossref","first-page":"37793","DOI":"10.1038\/srep37793","article-title":"New genome-wide algorithm identifies novel in-vivo expressed Mycobacterium tuberculosis antigens inducing human T-cell responses with classical and unconventional cytokine profiles","volume":"6","author":"Coppola","year":"2016","journal-title":"Sci. Rep."},{"key":"2025030610145589700_r37","doi-asserted-by":"crossref","first-page":"e0186998","DOI":"10.1371\/journal.pone.0186998","article-title":"Comparative analysis of activation induced marker (AIM) assays for sensitive identification of antigen-specific CD4 T cells","volume":"12","author":"Reiss","year":"2017","journal-title":"PLoS One"},{"key":"2025030610145589700_r38","doi-asserted-by":"crossref","first-page":"3358","DOI":"10.1128\/IAI.00014-11","article-title":"Mycobacterium tuberculosis culture filtrate protein 10-specific effector\/memory CD4+ and CD8+ T cells in tubercular pleural fluid, with biased usage of T cell receptor V\u03b2 chains","volume":"79","author":"Qiao","year":"2011","journal-title":"Infect. Immun."},{"key":"2025030610145589700_r39","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/nm.2299","article-title":"Dominant TNF-\u03b1+ Mycobacterium tuberculosis-specific CD4+ T cell responses discriminate between latent infection and active disease","volume":"17","author":"Harari","year":"2011","journal-title":"Nat. Med."},{"key":"2025030610145589700_r40","doi-asserted-by":"crossref","first-page":"968","DOI":"10.3389\/fimmu.2017.00968","article-title":"Analysis of the phenotype of Mycobacterium tuberculosis-specific CD4+ T cells to discriminate latent from active tuberculosis in HIV-uninfected and HIV-infected individuals","volume":"8","author":"Riou","year":"2017","journal-title":"Front. Immunol."},{"key":"2025030610145589700_r41","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1146\/annurev-immunol-032414-112056","article-title":"Heterogeneity of human CD4(+) T cells against microbes","volume":"34","author":"Sallusto","year":"2016","journal-title":"Annu. Rev. Immunol."},{"key":"2025030610145589700_r42","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/j.1365-3083.2007.02040.x","article-title":"Expression and regulation of the CC-chemokine ligand 20 during human tuberculosis","volume":"67","author":"Lee","year":"2008","journal-title":"Scand. J. Immunol."},{"key":"2025030610145589700_r43","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.1365-2249.2010.04168.x","article-title":"CCL20 is overexpressed in Mycobacterium tuberculosis-infected monocytes and inhibits the production of reactive oxygen species (ROS)","volume":"162","author":"Rivero-Lezcano","year":"2010","journal-title":"Clin. Exp. Immunol."},{"key":"2025030610145589700_r44","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/nrc706","article-title":"Multidrug resistance in cancer: role of ATP-dependent transporters","volume":"2","author":"Gottesman","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"2025030610145589700_r45","doi-asserted-by":"crossref","first-page":"2826","DOI":"10.4161\/cc.7.18.6752","article-title":"Emerging functions of c-kit and its ligand stem cell factor in dendritic cells: regulators of T cell differentiation","volume":"7","author":"Ray","year":"2008","journal-title":"Cell Cycle"},{"key":"2025030610145589700_r46","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nm1766","article-title":"Activation of c-Kit in dendritic cells regulates T helper cell differentiation and allergic asthma","volume":"14","author":"Krishnamoorthy","year":"2008","journal-title":"Nat. Med."},{"key":"2025030610145589700_r47","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1073\/pnas.94.2.469","article-title":"The human A33 antigen is a transmembrane glycoprotein and a novel member of the immunoglobulin superfamily","volume":"94","author":"Heath","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030610145589700_r48","doi-asserted-by":"crossref","first-page":"2797","DOI":"10.1002\/eji.201343751","article-title":"The who\u2019s who of T-cell differentiation: human memory T-cell subsets","volume":"43","author":"Mahnke","year":"2013","journal-title":"Eur. J. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/200\/9\/3283\/62231750\/ji1800118.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/200\/9\/3283\/62231750\/ji1800118.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T05:42:31Z","timestamp":1741239751000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/200\/9\/3283\/7966182"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,1]]},"references-count":48,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2018,5,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1800118","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,5]]},"published":{"date-parts":[[2018,5,1]]}}}