{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T14:35:54Z","timestamp":1787668554380,"version":"build-2736575974"},"reference-count":40,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T00:00:00Z","timestamp":1665619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["81701555"],"award-info":[{"award-number":["81701555"]}]},{"name":"National Natural Science Foundation of China","award":["81871239"],"award-info":[{"award-number":["81871239"]}]},{"name":"National Natural Science Foundation of China","award":["81901600"],"award-info":[{"award-number":["81901600"]}]},{"name":"National Natural Science Foundation of China","award":["2018JQ8060"],"award-info":[{"award-number":["2018JQ8060"]}]},{"name":"Natural Science Basic Research Plan in Shaanxi Province of China","award":["81701555"],"award-info":[{"award-number":["81701555"]}]},{"name":"Natural Science Basic Research Plan in Shaanxi Province of China","award":["81871239"],"award-info":[{"award-number":["81871239"]}]},{"name":"Natural Science Basic Research Plan in Shaanxi Province of China","award":["81901600"],"award-info":[{"award-number":["81901600"]}]},{"name":"Natural Science Basic Research Plan in Shaanxi Province of China","award":["2018JQ8060"],"award-info":[{"award-number":["2018JQ8060"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Hantaan virus (HTNV) infection causes an epidemic of hemorrhagic fever with renal syndrome (HFRS) mainly in Asia. It is well known that T cells mediated anti-viral immune response. Although previous studies showed that double positive T (DP T) cells, a little portion of T lymphocytes, were involved in adaptive immune response during virus infection, their kinetic changes and roles in HTNV infection have not yet been explored. In this study, we characterized DP T cells from HFRS patients based on flow cytometry data combined with scRNA-seq data. We showed that HTNV infection caused the upregulation of DP T cells in the peripheral blood, which were correlated with disease stage. The scRNA-seq data clustered DP T cells, unraveled their gene expression profile, and estimated the ordering of these cells. The production of granzyme B and CD107a from DP T cells and the abundant TCR distribution indicated the anti-viral property of DP T cells. In conclusion, this study identified, for the first time, an accumulation of DP T cells in the peripheral blood of HFRS patients and suggested these DP T cells belonging to CD8+T cells lineage. The DP T cells shared the similar characteristics with cytotoxic T cells (CTL) and exerted an anti-viral role in HFRS.<\/jats:p>","DOI":"10.3390\/v14102243","type":"journal-article","created":{"date-parts":[[2022,10,14]],"date-time":"2022-10-14T01:44:13Z","timestamp":1665711853000},"page":"2243","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Increased CD4+CD8+ Double Positive T Cells during Hantaan Virus Infection"],"prefix":"10.3390","volume":"14","author":[{"given":"Huiyuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"Department of Immunology, School of Basic Medical Sciences, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazhen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6756-0219","authenticated-orcid":false,"given":"Kang","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunmei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"Department of Immunology, School of Basic Medical Sciences, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"Department of Pathogenic Biology, School of Basic Medical Sciences, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manling","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"},{"name":"Department of Immunology, School of Basic Medical Sciences, Yan\u2019an University, Yan\u2019an 716000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhou","family":"Jia","sequence":"additional","affiliation":[{"name":"Eighth Hospital of Xi\u2019an, Xi\u2019an 710061, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifeng","family":"Hu","sequence":"additional","affiliation":[{"name":"Center for Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi\u2019an 710038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, Xijing Hospital, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3614-0422","authenticated-orcid":false,"given":"Ran","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boquan","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihua","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4272-857X","authenticated-orcid":false,"given":"Yusi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Fang, L., Yan, L., Liang, S., de Vlas, S.J., Feng, D., Han, X., Zhao, W., Xu, B., Bian, L., and Yang, H. (2006). Spatial analysis of hemorrhagic fever with renal syndrome in China. BMC Infect. Dis., 6.","DOI":"10.1186\/1471-2334-6-77"},{"key":"ref_2","first-page":"95","article-title":"Haemorrhagic fever with renal syndrome: Literature review and distribution analysis in China","volume":"43","author":"Zou","year":"2016","journal-title":"Int. J. Infect. Dis. IJID Off. Publ. Int. Soc. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/s41598-017-18819-4","article-title":"Mapping the epidemic changes and risks of hemorrhagic fever with renal syndrome in Shaanxi Province, China, 2005\u20132016","volume":"8","author":"Liang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1128\/CMR.00062-09","article-title":"A global perspective on hantavirus ecology, epidemiology, and disease","volume":"23","author":"Jonsson","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3669","DOI":"10.1681\/ASN.2005050561","article-title":"Hantavirus infection","volume":"16","author":"Muranyi","year":"2005","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1080\/23744235.2019.1672887","article-title":"Elevated plasma interleukin 34 levels correlate with disease severity-reflecting parameters of patients with haemorrhagic fever with renal syndrome","volume":"51","author":"Tang","year":"2019","journal-title":"Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Zhang, C., Zhuang, R., Ma, Y., Zhang, Y., Yi, J., Yang, A., and Jin, B. (2015). IL-33\/ST2 correlates with severity of haemorrhagic fever with renal syndrome and regulates the inflammatory response in Hantaan virus-infected endothelial cells. PLoS Negl. Trop. Dis., 9.","DOI":"10.1371\/journal.pntd.0003514"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1089\/vim.2004.17.481","article-title":"Hantaviruses: Immunology, treatment, and prevention","volume":"17","author":"Maes","year":"2004","journal-title":"Viral Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/nri952","article-title":"Chromatin and CD4, CD8A and CD8B gene expression during thymic differentiation","volume":"2","author":"Kioussis","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Ma, Y., Yuan, B., Zhuang, R., Zhang, Y., Liu, B., Zhang, C., Zhang, Y., Yu, H., Yi, J., and Yang, A. (2015). Hantaan virus infection induces both Th1 and ThGranzyme B+ cell immune responses that associated with viral control and clinical outcome in humans. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004788"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ma, Y., Wang, J., Yuan, B., Wang, M., Zhang, Y., Xu, Z., Zhang, C., Zhang, Y., Liu, B., and Yi, J. (2013). HLA-A2 and B35 restricted hantaan virus nucleoprotein CD8+ T-cell epitope-specific immune response correlates with milder disease in hemorrhagic fever with renal syndrome. PLoS Negl. Trop. Dis., 7.","DOI":"10.1371\/journal.pntd.0002076"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1038\/s42003-021-02182-2","article-title":"HTNV infection of CD8(+) T cells is associated with disease progression in HFRS patients","volume":"4","author":"Liu","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1182\/blood.V82.5.1546.1546","article-title":"Persistent expansions of CD4+ CD8+ peripheral blood T cells","volume":"82","author":"Sala","year":"1993","journal-title":"Blood"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1006\/bbrc.1993.1260","article-title":"Cytofluorimetric identification of two populations of double positive (CD4+,CD8+) T lymphocytes in human peripheral blood","volume":"191","author":"Ortolani","year":"1993","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.4049\/jimmunol.134.4.2281","article-title":"Coexpression of T4 and T8 on peripheral blood T cells demonstrated by two-color fluorescence flow cytometry","volume":"134","author":"Blue","year":"1985","journal-title":"J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1111\/j.1365-2141.2007.06867.x","article-title":"Age-dependent accumulation of monoclonal CD4+CD8+ double positive T lymphocytes in the peripheral blood of the elderly","volume":"139","author":"Ghia","year":"2007","journal-title":"Br. J. Haematol."},{"key":"ref_17","first-page":"125","article-title":"Percentages and Absolute Numbers of CD4+CD8+ Double-positive T Lymphocytes in the Peripheral Blood of Normal Italian Subjects: Relationship with Age and Sex","volume":"37","author":"Marini","year":"2020","journal-title":"Turk. J. Haematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11555","DOI":"10.1128\/JVI.75.23.11555-11564.2001","article-title":"Activated peripheral CD8 lymphocytes express CD4 in vivo and are targets for infection by human immunodeficiency virus type 1","volume":"75","author":"Imlach","year":"2001","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/349533a0","article-title":"Induction of CD4 and susceptibility to HIV-1 infection in human CD8+ T lymphocytes by human herpesvirus 6","volume":"349","author":"Lusso","year":"1991","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1006\/cimm.1993.1163","article-title":"Emergence of double-positive CD4\/CD8 cells from adult peripheral blood mononuclear cells infected with human T cell leukemia virus type I (HTLV-I)","volume":"149","author":"Macchi","year":"1993","journal-title":"Cell Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3794","DOI":"10.1073\/pnas.0406603102","article-title":"The CD4 molecule on CD8+ T lymphocytes directly enhances the immune response to viral and cellular antigens","volume":"102","author":"Kitchen","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5646","DOI":"10.1128\/jvi.70.8.5646-5650.1996","article-title":"Simian immunodeficiency virus infection of CD8+ lymphocytes in vivo","volume":"70","author":"Dean","year":"1996","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Yu, E.D., Wang, H., Antunes, R.d., Tian, Y., Tippalagama, R., Alahakoon, S.U., Premawansa, G., Wijewickrama, A., Premawansa, S., and de Silva, A.D. (2022). A Population of CD4(+)CD8(+) Double-Positive T Cells Associated with Risk of Plasma Leakage in Dengue Viral Infection. Viruses, 14.","DOI":"10.3390\/v14010090"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Quandt, D., Rothe, K., Scholz, R., Baerwald, C.W., and Wagner, U. (2014). Peripheral CD4CD8 double positive T cells with a distinct helper cytokine profile are increased in rheumatoid arthritis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0093293"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Giraldo, N.A., Bolanos, N.I., Cuellar, A., Guzman, F., Uribe, A.M., Bedoya, A., Olaya, N., Cucunuba, Z.M., Roa, N., and Rosas, F. (2011). Increased CD4+\/CD8+ double-positive T cells in chronic Chagasic patients. PLoS Negl. Trop. Dis., 5.","DOI":"10.1371\/journal.pntd.0001294"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Desfrancois, J., Moreau-Aubry, A., Vignard, V., Godet, Y., Khammari, A., Dreno, B., Jotereau, F., and Gervois, N. (2010). Double positive CD4CD8 alphabeta T cells: A new tumor-reactive population in human melanomas. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0008437"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"184","DOI":"10.4049\/jimmunol.1201163","article-title":"Isolation of human CD4\/CD8 double-positive, graft-versus-host disease-protective, minor histocompatibility antigen-specific regulatory T cells and of a novel HLA-DR7-restricted HY-specific CD4 clone","volume":"190","author":"Eljaafari","year":"2013","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2728","DOI":"10.3389\/fimmu.2018.02728","article-title":"Renal Cell Carcinoma (RCC) Tumors Display Large Expansion of Double Positive (DP) CD4+CD8+ T Cells With Expression of Exhaustion Markers","volume":"9","author":"Menard","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"665410","DOI":"10.3389\/fmed.2021.665410","article-title":"The Presence of Circulating Nucleated Red Blood Cells Is Associated With Disease Severity in Patients of Hemorrhagic Fever With Renal Syndrome","volume":"8","author":"Zhang","year":"2021","journal-title":"Front. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3002","DOI":"10.3389\/fimmu.2019.03002","article-title":"CD8(+) T Cells Form the Predominant Subset of NKG2A(+) Cells in Human Lung Cancer","volume":"10","author":"Chen","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3109\/10428199809050932","article-title":"The role of interleukin-7 in early T-cell development","volume":"30","author":"Offner","year":"1998","journal-title":"Leuk. Lymphoma"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3028","DOI":"10.1101\/gad.10.23.3028","article-title":"The protein that binds the 3\u2032 end of histone mRNA: A novel RNA-binding protein required for histone pre-mRNA processing","volume":"10","author":"Wang","year":"1996","journal-title":"Genes Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1189\/jlb.1RU0814-382","article-title":"CD4+\/CD8+ double-positive T cells: More than just a developmental stage?","volume":"97","author":"Overgaard","year":"2015","journal-title":"J. Leukoc. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.immuni.2008.09.019","article-title":"The zinc finger transcription factor Zbtb7b represses CD8-lineage gene expression in peripheral CD4+ T cells","volume":"29","author":"Wang","year":"2008","journal-title":"Immunity"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1126\/science.1151844","article-title":"Repression of the transcription factor Th-POK by Runx complexes in cytotoxic T cell development","volume":"319","author":"Setoguchi","year":"2008","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1002\/eji.200535520","article-title":"Intestinal double-positive CD4+CD8+ T cells are highly activated memory cells with an increased capacity to produce cytokines","volume":"36","author":"Pahar","year":"2006","journal-title":"Eur. J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1086\/515674","article-title":"Persistent expansion, in a human immunodeficiency virus-infected person, of V beta-restricted CD4+CD8+ T lymphocytes that express cytotoxicity-associated molecules and are committed to produce interferon-gamma and tumor necrosis factor-alpha","volume":"178","author":"Weiss","year":"1998","journal-title":"J. Infect. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/sj.leu.2400978","article-title":"Phenotypical heterogeneity of CD4+CD8+ double-positive chronic T lymphoid leukemia","volume":"12","author":"Mizuki","year":"1998","journal-title":"Leukemia"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.1073\/pnas.95.6.3111","article-title":"Activation of CD8+ T lymphocytes through the T cell receptor turns on CD4 gene expression: Implications for HIV pathogenesis","volume":"95","author":"Flamand","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/j.humimm.2019.09.008","article-title":"Double positive CD4+CD8+ T cells are part of the adaptive immune response against Candida albicans","volume":"80","author":"Touahri","year":"2019","journal-title":"Hum. Immunol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/10\/2243\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:53:05Z","timestamp":1760143985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/10\/2243"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,13]]},"references-count":40,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["v14102243"],"URL":"https:\/\/doi.org\/10.3390\/v14102243","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,13]]}}}