{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:30:21Z","timestamp":1789428621619,"version":"build-2803163510"},"reference-count":42,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T00:00:00Z","timestamp":1641945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF-2016-02364155"],"award-info":[{"award-number":["RF-2016-02364155"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della salute","doi-asserted-by":"publisher","award":["Ricerca Corrente - Linea 1"],"award-info":[{"award-number":["Ricerca Corrente - Linea 1"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>\u03b3\u03b4 T cells are innate cells able to quickly eliminate pathogens or infected\/tumoral cells by their antiviral and adjuvancy activities. The role of \u03b3\u03b4 T cells during Dengue Viral Infection (DENV) infection is not fully elucidated. Nevertheless, human primary \u03b3\u03b4 T cells have been shown to kill in vitro DENV-infected cells, thus highlighting their possible antiviral function. The aim of this work was to characterize the phenotype and function of V\u03b42 T cells in DENV patients. Fifteen DENV patients were enrolled for this study and peripheral blood mononuclear cells (PBMC) were used to analyze V\u03b42-T-cell frequency, differentiation profile, activation\/exhaustion status, and functionality by multiparametric flow cytometry. Our data demonstrated that DENV infection was able to significantly reduce V\u03b42-T-cell frequency and to increase their activation (CD38 and HLA-DR) and exhaustion markers (PD-1 and TIM-3). Furthermore, V\u03b42 T cells showed a reduced capability to produce IFN-\u03b3 after phosphoantigenic stimulation that can be associated to TIM-3 expression. Several studies are needed to depict the possible clinical impact of \u03b3\u03b4-T-cell impairment on disease severity and to define the antiviral and immunoregulatory activities of \u03b3\u03b4 T cells in the first phases of infection.<\/jats:p>","DOI":"10.3390\/v14010130","type":"journal-article","created":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T09:10:36Z","timestamp":1641978636000},"page":"130","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["In Acute Dengue Infection, High TIM-3 Expression May Contribute to the Impairment of IFN\u03b3 Production by Circulating V\u03b42 T Cells"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2659-0868","authenticated-orcid":false,"given":"Eleonora","family":"Cimini","sequence":"first","affiliation":[{"name":"Laboratory of Cellular Immunology and Pharmacology, National Institute for Infectious Diseases \u201cL. Spallanzani\u201d, Via Portuense 292, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8168-8721","authenticated-orcid":false,"given":"Germana","family":"Grassi","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Immunology and Pharmacology, National Institute for Infectious Diseases \u201cL. Spallanzani\u201d, Via Portuense 292, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Beccacece","sequence":"additional","affiliation":[{"name":"Clinical Department, National Institute for Infectious Diseases \u201cL. Spallanzani\u201d, Via Portuense 292, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Casetti","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Immunology and Pharmacology, National Institute for Infectious Diseases \u201cL. Spallanzani\u201d, Via Portuense 292, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9819-236X","authenticated-orcid":false,"given":"Concetta","family":"Castilletti","sequence":"additional","affiliation":[{"name":"Laboratory of Virology, National Institute for Infectious Diseases \u201cL. Spallanzani\u201d, Via Portuense 292, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Capobianchi","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Pre-Clinical Research and Advanced Diagnostic, National Institute for Infectious Diseases \u201cL. Spallanzani\u201d, Via Portuense 292, 00149 Rome, Italy"},{"name":"Saint Camillus International University of Health Sciences, Via di Sant\u2019Alessandro, 8, 00131 Roma, Italy"},{"name":"Department of Infectious Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, Via Don A. Sempreboni 5, 37024 Negrar di Valpolicella, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5606-8712","authenticated-orcid":false,"given":"Emanuele","family":"Nicastri","sequence":"additional","affiliation":[{"name":"Clinical Department, National Institute for Infectious Diseases \u201cL. Spallanzani\u201d, Via Portuense 292, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5252-0927","authenticated-orcid":false,"given":"Chiara","family":"Agrati","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Immunology and Pharmacology, National Institute for Infectious Diseases \u201cL. Spallanzani\u201d, Via Portuense 292, 00149 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"666983","DOI":"10.3389\/fimmu.2021.666983","article-title":"How to Train Your Dragon: Harnessing Gamma Delta T Cells Antiviral Functions and Trained Immunity in a Pandemic Era","volume":"12","author":"Caron","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/nri.2017.101","article-title":"\u03b3\u03b4 T cells in homeostasis and host defence of epithelial barrier tissues","volume":"17","author":"Nielsen","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1084\/jem.171.5.1597","article-title":"Evidence for extrathymic changes in the T cell receptor gamma\/delta repertoire","volume":"171","author":"Parker","year":"1990","journal-title":"J. Exp. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.3389\/fimmu.2018.02636","article-title":"Tissue Adaptations of Memory and Tissue-Resident Gamma Delta T Cells","volume":"9","author":"Khairallah","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Cimini, E., Sacchi, A., De Minicis, S., Bordoni, V., Casetti, R., Grassi, G., Colavita, F., Castilletti, C., Capobianchi, M.R., and Ippolito, G. (2019). V\u03b42 T-Cells Kill ZIKV-Infected Cells by NKG2D-Mediated Cytotoxicity. Microorganisms, 7.","DOI":"10.3390\/microorganisms7090350"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.virusres.2017.10.008","article-title":"Intrahepatic V\u03b39V\u03b42 T-cells from HCV-infected patients show an exhausted phenotype but can inhibit HCV replication","volume":"243","author":"Cimini","year":"2018","journal-title":"Virus Res."},{"key":"ref_7","first-page":"139","article-title":"Antiviral activity of human V\u03b42 T-cells against WNV includes both cytolytic and non-cytolytic mechanisms","volume":"39","author":"Agrati","year":"2016","journal-title":"New Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bank, I. (2020). The Role of Gamma Delta T Cells in Autoimmune Rheumatic Diseases. Cells, 9.","DOI":"10.3390\/cells9020462"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.jneuroim.2019.02.009","article-title":"\u03b3\u03b4 T lymphocytes in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis","volume":"330","author":"Zarobkiewicz","year":"2019","journal-title":"J. Neuroimmunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.3389\/fimmu.2018.02389","article-title":"\u03b3\u03b4 T Lymphocytes: An Effector Cell in Autoimmunity and Infection","volume":"9","author":"Shiromizu","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1016\/j.jaci.2020.11.023","article-title":"Dissecting the complexity of \u03b3\u03b4 T-cell subsets in skin homeostasis, inflammation, and malignancy","volume":"147","author":"Cibrian","year":"2021","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1007\/s00005-021-00608-7","article-title":"\u03b3\u03b4 T Lymphocytes in Asthma: A Complicated Picture","volume":"69","author":"Zarobkiewicz","year":"2021","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Miyashita, M., Shimizu, T., Ashihara, E., and Ukimura, O. (2021). Strategies to Improve the Antitumor Effect of \u03b3\u03b4 T Cell Immunotherapy for Clinical Application. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168910"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"302","DOI":"10.3389\/fimmu.2015.00302","article-title":"Role of Innate T Cells in Anti-Bacterial Immunity","volume":"6","author":"Gao","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1186\/s12985-020-01449-0","article-title":"Role of gammadelta T cells in controlling viral infections with a focus on influenza virus: Implications for designing novel therapeutic approaches","volume":"17","author":"Sabbaghi","year":"2020","journal-title":"Virol. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.imlet.2005.06.025","article-title":"V\u03b39V\u03b42 T cell-mediated non-cytolytic antiviral mechanisms and their potential for cell-based therapy","volume":"100","author":"Poccia","year":"2005","journal-title":"Immunol. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1086\/503438","article-title":"Interferon-\u03b3\u2013Mediated Antiviral Immunity against Orthopoxvirus Infection Is Provided by \u03b3\u03b4 T Cells","volume":"193","author":"Agrati","year":"2006","journal-title":"J. Infect. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1093\/intimm\/dxh337","article-title":"Activation of V\u03b39V\u03b42 T cells by non-peptidic antigens induces the inhibition of subgenomic HCV replication","volume":"18","author":"Agrati","year":"2005","journal-title":"Int. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1086\/502975","article-title":"Anti\u2013Severe Acute Respiratory Syndrome Coronavirus Immune Responses: The Role Played by V\u03b39V\u03b42 T Cells","volume":"193","author":"Poccia","year":"2006","journal-title":"J. Infect. Dis."},{"key":"ref_20","first-page":"3","article-title":"Innate gamma\/delta T-cells during HIV infection: Terra relatively Incognita in novel vaccination strategies?","volume":"13","author":"Agrati","year":"2011","journal-title":"AIDS Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"22487","DOI":"10.1021\/acsomega.1c03536","article-title":"Overview of Pathogenesis, Diagnostics, and Therapeutics of Infectious Diseases: Dengue and Zika","volume":"6","author":"Jayachandran","year":"2021","journal-title":"ACS Omega"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"16055","DOI":"10.1038\/nrdp.2016.55","article-title":"Dengue infection","volume":"2","author":"Guzman","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3890","DOI":"10.4049\/jimmunol.1303343","article-title":"Type I IFNs and IL-18 Regulate the Antiviral Response of Primary Human \u03b3\u03b4 T Cells against Dendritic Cells Infected with Dengue Virus","volume":"194","author":"Tsai","year":"2015","journal-title":"J. Immunol."},{"key":"ref_24","unstructured":"(2016, April 07). CDC DENV-1-4 Real-Time RT-PCR Assay, Available online: https:\/\/www.cdc.gov\/dengue\/healthcare-providers\/testing\/molecular-tests\/realtime.html."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1186\/1743-422X-10-311","article-title":"Quantitative real-time PCR detection of Zika virus and evaluation with field-caught Mosquitoes","volume":"10","author":"Faye","year":"2013","journal-title":"Virol. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jviromet.2004.11.002","article-title":"Development of a TaqMan\u00ae RT-PCR assay without RNA extraction step for the detection and quantification of African Chikungunya viruses","volume":"124","author":"Pastorino","year":"2005","journal-title":"J. Virol. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6313","DOI":"10.1038\/s41598-017-06536-x","article-title":"Human Zika infection induces a reduction of IFN-\u03b3 producing CD4 T-cells and a parallel expansion of effector V\u03b42 T-cells","volume":"7","author":"Cimini","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/s41426-018-0168-0","article-title":"Dengue virus and the host innate immune response","volume":"7","author":"Uno","year":"2018","journal-title":"Emerg. Microbes Infect."},{"key":"ref_29","first-page":"209","article-title":"Control of Acute Dengue Virus Infection by Natural Killer Cells","volume":"5","author":"Epetitdemange","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1111\/j.1365-2249.2006.02996.x","article-title":"NK cells, displaying early activation, cytotoxicity and adhesion molecules, are associated with mild dengue disease","volume":"143","author":"Azeredo","year":"2006","journal-title":"Clin. Exp. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1172\/JCI122530","article-title":"Immune synapses between mast cells and \u03b3\u03b4 T cells limit viral infection","volume":"129","author":"Mantri","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e2164","DOI":"10.1038\/cddis.2016.55","article-title":"Longitudinal characterization of dysfunctional T cell-activation during human acute Ebola infection","volume":"7","author":"Agrati","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Cimini, E., Viola, D., Cabeza-Cabrerizo, M., Romanelli, A., Tumino, N., Sacchi, A., Bordoni, V., Casetti, R., Turchi, F., and Martini, F. (2017). Different features of V\u03b42 T and NK cells in fatal and non-fatal human Ebola infections. PLoS Negl. Trop. Dis., 11.","DOI":"10.1371\/journal.pntd.0005645"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3434","DOI":"10.1038\/s41467-020-17292-4","article-title":"Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia","volume":"11","author":"Meschiari","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_35","first-page":"17","article-title":"Role of PD-1 in Regulating T-Cell Immunity","volume":"350","author":"Jin","year":"2010","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1016\/j.molcel.2020.02.013","article-title":"PD-1: A Driver or Passenger of T Cell Exhaustion?","volume":"77","author":"He","year":"2020","journal-title":"Mol. Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1002\/eji.201040959","article-title":"Expression and function of PD-1 in human \u03b3\u03b4 T cells that recognize phosphoantigens","volume":"41","author":"Iwasaki","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1073\/pnas.1712107115","article-title":"Tim-3 co-stimulation promotes short-lived effector T cells, restricts memory precursors, and is dispensable for T cell exhaustion","volume":"115","author":"Avery","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"449","DOI":"10.3389\/fimmu.2013.00449","article-title":"Tim-3: An Activation Marker and Activation Limiter of Innate Immune Cells","volume":"4","author":"Han","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Catafal-Tardos, E., Baglioni, M.V., and Bekiaris, V. (2021). Inhibiting the Unconventionals: Importance of Immune Checkpoint Receptors in \u03b3\u03b4 T, MAIT, and NKT Cells. Cancers, 13.","DOI":"10.3390\/cancers13184647"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Schofield, L., Ioannidis, L.J., Karl, S., Robinson, L.J., Tan, Q.Y., Poole, D.P., Betuela, I., Hill, D.L., Siba, P.M., and Hansen, D.S. (2017). Synergistic effect of IL-12 and IL-18 induces TIM3 regulation of \u03b3\u03b4 T cell function and decreases the risk of clinical malaria in children living in Papua New Guinea. BMC Med., 15.","DOI":"10.1186\/s12916-017-0883-8"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"111719","DOI":"10.1016\/j.yexcr.2019.111719","article-title":"Tim-3 suppresses the killing effect of V\u03b39V\u03b42 T cells on colon cancer cells by reducing perforin and granzyme B expression","volume":"386","author":"Li","year":"2020","journal-title":"Exp. Cell Res."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/1\/130\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:27:21Z","timestamp":1760362041000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/1\/130"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,12]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["v14010130"],"URL":"https:\/\/doi.org\/10.3390\/v14010130","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,12]]}}}