{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T12:16:58Z","timestamp":1789129018955,"version":"build-2803163510"},"reference-count":65,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T00:00:00Z","timestamp":1721174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T00:00:00Z","timestamp":1721174400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32070149, 32270138, 31770178"],"award-info":[{"award-number":["32070149, 32270138, 31770178"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32370150"],"award-info":[{"award-number":["32370150"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004024","name":"Jinan University","doi-asserted-by":"crossref","award":["2023CXB015"],"award-info":[{"award-number":["2023CXB015"]}],"id":[{"id":"10.13039\/501100004024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2024,7,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>Human cytomegalovirus (HCMV), a widely prevalent human beta-herpesvirus, establishes lifelong persistence in the host following primary infection. In healthy individuals, the virus is effectively controlled by HCMV-specific T cells and typically exhibits asymptomatic. The T cell immune response plays a pivotal role in combating HCMV infection, while HCMV employs various strategies to counteract it within the host. Previously, we reported that UL23, a tegument protein of HCMV, facilitates viral immune evasion from interferon-gamma (IFN-\u03b3) responses, and it is well known that IFN-\u03b3 is mainly derived from T cells. However, the involvement of UL23 in viral immune evasion from T cell-mediated immunity remains unclear. Herein, we present compelling evidence that UL23 significantly enhances viral resistance against T cell-mediated cytotoxicity during HCMV infection from the co-culture assays of HCMV-infected cells with T cells. We found that IFN-\u03b3 plays a major role in regulating T cell cytotoxicity mediated by UL23. More interestingly, we demonstrated that UL23 not only regulates the IFN-\u03b3 downstream responses but also modulates the IFN-\u03b3 secretion by regulating T cell activities. Further experiments indicate that UL23 upregulates the expression and signaling of programmed death ligand 1 (PD-L1), which is responsible for inhibiting multiple aspects of T cell activities, including activation, apoptosis, and IFN-\u03b3 secretion, as determined through RNA-seq analysis and inhibitor-blocking experiments, ultimately facilitating viral replication and spread. Our findings highlight the potential role of UL23 as an alternative antagonist in suppressing T cell cytotoxicity and unveil a novel strategy for HCMV to evade T cell immunity.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>T cell immunity is pivotal in controlling primary human cytomegalovirus (HCMV) infection, restricting periodic reactivation, and preventing HCMV-associated diseases. Despite inducing a robust T cell immune response, HCMV has developed sophisticated immune evasion mechanisms that specifically target T cell responses. Although numerous studies have been conducted on HCMV-specific T cells, the primary focus has been on the impact of HCMV on T cell recognition via major histocompatibility complex molecules. Our studies show for the first time that HCMV exploits the programmed death ligand 1 (PD-L1) inhibitory signaling pathway to evade T cell immunity by modulating the activities of T cells and thereby blocking the secretion of IFN-\u03b3, which is directly mediated by HCMV-encoded tegument protein UL23. While PD-L1 has been extensively studied in the context of tumors and viruses, its involvement in HCMV infection and viral immune evasion is rarely reported. We observed an upregulation of PD-L1 in normal cells during HCMV infection and provided strong evidence supporting its critical role in UL23-induced inhibition of T cell-mediated cytotoxicity. The novel strategy employed by HCMV to manipulate the inhibitory signaling pathway of T cell immune activation for viral evasion through its encoded protein offers valuable insights for the understanding of HCMV-mediated T cell immunomodulation and developing innovative antiviral treatment strategies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.01191-24","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T13:02:29Z","timestamp":1717419749000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["Human cytomegalovirus UL23 exploits PD-L1 inhibitory signaling pathway to evade T cell-mediated cytotoxicity"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7136-0277","authenticated-orcid":false,"given":"Qin","family":"Yuan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China"},{"name":"Key Laboratory of Viral Pathogenesis &amp; Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, China"},{"name":"Department of Biological Sciences and Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaosong","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Huo","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8657-3405","authenticated-orcid":true,"given":"Yanhong","family":"Ran","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2447-0544","authenticated-orcid":true,"given":"Jun","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China"},{"name":"Key Laboratory of Viral Pathogenesis &amp; Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2143-7079","authenticated-orcid":false,"given":"Hongjian","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China"},{"name":"Key Laboratory of Viral Pathogenesis &amp; Infection Prevention and Control (Jinan University), Ministry of Education, Guangzhou, China"},{"name":"Department of Biological Sciences and Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.2034"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.4437"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-021-00582-z"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2006.01488.x"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V104.11.5087.5087"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.00202"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/648423"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0106044"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis818"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050882"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v99.11.3916"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)14634-X"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.3390\/v13081563"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02117-09"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-018-1394-x"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01155"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20153626"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2014.105"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.152147499"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02946-22"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006454"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-83-6-1315"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006867"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2009.02.004"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.03.014"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22094893"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-03140-2"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2334032100"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2017.04.002"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-023-00570-7"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-0685"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-021-02069-4"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1081\/imm-120030732"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-1091-2"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10120-023-01429-7"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-16104-4"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.38"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01129"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02128-16"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abe6968"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2016.00844"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.02.033"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1330"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.3390\/v13122355"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01059-3"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1914667117"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2016.49"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2019.00207"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0928-4"},{"key":"e_1_3_3_51_2","first-page":"5318","article-title":"TLR3 regulates PD-L1 expression in human cytomegalovirus infected glioblastoma","volume":"11","author":"Qin Z","year":"2018","unstructured":"Qin Z, Zhang L, Xu Y, Zhang X, Fang X, Qian D, Liu X, Liu T, Li L, Yu H, Wang B. 2018. TLR3 regulates PD-L1 expression in human cytomegalovirus infected glioblastoma. Int J Clin Exp Pathol 11:5318\u20135326.","journal-title":"Int J Clin Exp Pathol"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2020.08.060"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-041015-055318"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01224-z"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12823"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-020-00170-8"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-017-9984-8"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2016.02111"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00179-16"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02044-20"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.41.8.3840-3845.2003"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22173-5"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-020-0048-0"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.04.031"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15364-z"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02560"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.01191-24","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mbio.01191-24","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T13:02:19Z","timestamp":1721221339000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mbio.01191-24"}},"subtitle":[],"editor":[{"given":"Yung-Fu","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,7,17]]},"references-count":65,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024,7,17]]}},"alternative-id":["10.1128\/mbio.01191-24"],"URL":"https:\/\/doi.org\/10.1128\/mbio.01191-24","relation":{},"ISSN":["2150-7511"],"issn-type":[{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,17]]},"assertion":[{"value":"2024-04-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01191-24"}}