{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:58Z","timestamp":1787028538884,"version":"build-2736575974"},"reference-count":60,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T00:00:00Z","timestamp":1712793600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["AI128442"],"award-info":[{"award-number":["AI128442"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We have recently reported that transcription factor Runx3 is required for pulmonary generation of CD8+ cytotoxic T lymphocytes (CTLs) that play a crucial role in the clearance of influenza A virus (IAV). To understand the underlying mechanisms, we determined the effects of Runx3 knockout (KO) on CD8+ T cell local expansion and phenotypes using an inducible general Runx3 KO mouse model. We found that in contrast to the lungs, Runx3 general KO promoted enlargement of lung-draining mediastinal lymph node (mLN) and enhanced CD8+ and CD4+ T cell expansion during H1N1 IAV infection. We further found that Runx3 deficiency greatly inhibited core 2 O-glycosylation of selectin ligand CD43 on activated CD8+ T cells but minimally affected the cell surface expression of CD43, activation markers (CD44 and CD69) and cell adhesion molecules (CD11a and CD54). Runx3 KO had a minor effect on lung effector CD8+ T cell death by IAV infection. Our findings indicate that Runx3 differently regulates CD8+ T cell expansion in mLNs and lungs by H1N1 IAV infection. Runx3 is required for CD43 core 2 O-glycosylation on activated CD8+ T cells, and the involved Runx3 signal pathway may mediate CD8+ T cell phenotype for pulmonary generation of CTLs.<\/jats:p>","DOI":"10.3390\/ijms25084220","type":"journal-article","created":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T03:29:04Z","timestamp":1712806144000},"page":"4220","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Runx3 Regulates CD8+ T Cell Local Expansion and CD43 Glycosylation in Mice by H1N1 Influenza A Virus Infection"],"prefix":"10.3390","volume":"25","author":[{"given":"Qin","family":"Hao","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8591-1166","authenticated-orcid":false,"given":"Suman","family":"Kundu","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sreerama","family":"Shetty","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6886-7450","authenticated-orcid":false,"given":"Hua","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1016\/j.ijcard.2013.01.274","article-title":"The cardiovascular manifestations of influenza: A systematic review","volume":"167","author":"Estabragh","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S1473-3099(13)70286-X","article-title":"Pathogenesis of influenza-induced acute respiratory distress syndrome","volume":"14","author":"Short","year":"2014","journal-title":"Lancet Infect. Dis."},{"key":"ref_3","first-page":"S132","article-title":"Influenza A induced cellular signal transduction pathways","volume":"5","author":"Michael","year":"2013","journal-title":"J. Thorac. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/ni1343","article-title":"Influenza and the challenge for immunology","volume":"7","author":"Doherty","year":"2006","journal-title":"Nat. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"236","DOI":"10.7883\/yoken.JJID.2004.236","article-title":"Defense mechanisms against influenza virus infection in the respiratory tract mucosa","volume":"57","author":"Tamura","year":"2004","journal-title":"Jpn. J. Infect. Dis."},{"key":"ref_6","first-page":"423","article-title":"The effector T cell response to influenza infection","volume":"386","author":"Hufford","year":"2015","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.coviro.2013.05.001","article-title":"Role of T cell immunity in recovery from influenza virus infection","volume":"3","author":"Sun","year":"2013","journal-title":"Curr. Opin. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"678","DOI":"10.3389\/fimmu.2018.00678","article-title":"The CD8 T Cell Response to Respiratory Virus Infections","volume":"9","author":"Schmidt","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5648","DOI":"10.1128\/JVI.72.7.5648-5653.1998","article-title":"Protective CD4+ and CD8+ T cells against influenza virus induced by vaccination with nucleoprotein DNA","volume":"72","author":"Ulmer","year":"1998","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.vaccine.2006.08.036","article-title":"Primary influenza A virus infection induces cross-protective immunity against a lethal infection with a heterosubtypic virus strain in mice","volume":"25","author":"Kreijtz","year":"2007","journal-title":"Vaccine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4983","DOI":"10.1016\/j.vaccine.2009.05.079","article-title":"Infection of mice with a human influenza A\/H3N2 virus induces protective immunity against lethal infection with influenza A\/H5N1 virus","volume":"27","author":"Kreijtz","year":"2009","journal-title":"Vaccine"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1093\/infdis\/jiz583","article-title":"Early Induction of Cross-Reactive CD8+ T-Cell Responses in Tonsils After Live-Attenuated Influenza Vaccination in Children","volume":"221","author":"Mohn","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kim, T.S., and Braciale, T.J. (2009). Respiratory dendritic cell subsets differ in their capacity to support the induction of virus-specific cytotoxic CD8+ T cell responses. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0004204"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.1007\/s00018-015-1835-0","article-title":"Molecular mechanisms of CD8(+) T cell trafficking and localization","volume":"72","author":"Nolz","year":"2015","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"600","DOI":"10.3389\/fimmu.2017.00600","article-title":"Regulation of T Cell Trafficking by Enzymatic Synthesis of O-Glycans","volume":"8","author":"Hobbs","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.coviro.2017.10.001","article-title":"Activation and trafficking of CD8(+) T cells during viral skin infection: Immunological lessons learned from vaccinia virus","volume":"28","author":"Hobbs","year":"2018","journal-title":"Curr. Opin. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.2217\/imt.11.100","article-title":"Naive, effector and memory CD8 T-cell trafficking: Parallels and distinctions","volume":"3","author":"Nolz","year":"2011","journal-title":"Immunotherapy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1038\/ni1002-903","article-title":"Sweet \u2018n\u2019 sour: The impact of differential glycosylation on T cell responses","volume":"3","author":"Daniels","year":"2002","journal-title":"Nat. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1172\/JCI72039","article-title":"IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking","volume":"124","author":"Nolz","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"eaan6049","DOI":"10.1126\/sciimmunol.aan6049","article-title":"Enzymatic synthesis of core 2 O-glycans governs the tissue-trafficking potential of memory CD8(+) T cells","volume":"2","author":"Osborn","year":"2017","journal-title":"Sci. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6841","DOI":"10.4049\/jimmunol.167.12.6841","article-title":"IL-2, -4, and -15 differentially regulate O-glycan branching and P-selectin ligand formation in activated CD8 T cells","volume":"167","author":"Carlow","year":"2001","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1111\/j.1749-6632.2011.06304.x","article-title":"T cells modulate glycans on CD43 and CD45 during development and activation, signal regulation, and survival","volume":"1253","author":"Clark","year":"2012","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.4049\/jimmunol.1901194","article-title":"GCNT1-Mediated O-Glycosylation of the Sialomucin CD43 Is a Sensitive Indicator of Notch Signaling in Activated T Cells","volume":"204","author":"Perkey","year":"2020","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/978-3-319-89512-3_17","article-title":"Notch and T Cell Function\u2014A Complex Tale","volume":"1066","author":"Vijayaraghavan","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5654","DOI":"10.4049\/jimmunol.1402837","article-title":"The Notch signaling pathway controls short-lived effector CD8+ T cell differentiation but is dispensable for memory generation","volume":"194","author":"Mathieu","year":"2015","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1038\/ni.3027","article-title":"A central role for Notch in effector CD8(+) T cell differentiation","volume":"15","author":"Backer","year":"2014","journal-title":"Nat. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"643","DOI":"10.4049\/jimmunol.1601715","article-title":"T Cell-Restricted Notch Signaling Contributes to Pulmonary Th1 and Th2 Immunity during Cryptococcus neoformans Infection","volume":"199","author":"Neal","year":"2017","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Auderset, F., Schuster, S., Coutaz, M., Koch, U., Desgranges, F., Merck, E., MacDonald, H.R., Radtke, F., and Tacchini-Cottier, F. (2012). Redundant Notch1 and Notch2 signaling is necessary for IFNgamma secretion by T helper 1 cells during infection with Leishmania major. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002560"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7731","DOI":"10.1073\/pnas.1232420100","article-title":"Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis","volume":"100","author":"Woolf","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"16016","DOI":"10.1073\/pnas.0407180101","article-title":"Loss of Runx3 function in leukocytes is associated with spontaneously developed colitis and gastric mucosal hyperplasia","volume":"101","author":"Brenner","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0092-8674(02)00690-6","article-title":"Causal relationship between the loss of RUNX3 expression and gastric cancer","volume":"109","author":"Li","year":"2002","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1011922","DOI":"10.3389\/fimmu.2022.1011922","article-title":"Inducible general knockout of Runx3 profoundly reduces pulmonary cytotoxic CD8(+) T cells with minimal effect on outcomes in mice following influenza infection","volume":"13","author":"Hao","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/S0378-1119(01)00760-0","article-title":"The RUNX3 gene--sequence, structure and regulated expression","volume":"279","author":"Bangsow","year":"2001","journal-title":"Gene"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1093\/glycob\/7.1.129","article-title":"Modification of CD43 and other lymphocyte O-glycoproteins by core 2 N-acetylglucosaminyltransferase","volume":"7","author":"Barran","year":"1997","journal-title":"Glycobiology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.immuni.2014.02.004","article-title":"Distinct dendritic cell subsets dictate the fate decision between effector and memory CD8(+) T cell differentiation by a CD24-dependent mechanism","volume":"40","author":"Kim","year":"2014","journal-title":"Immunity"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1084\/jem.191.7.1241","article-title":"Differentiating between memory and effector CD8 T cells by altered expression of cell surface O-glycans","volume":"191","author":"Harrington","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/ni.3773","article-title":"The transcription factor Runx3 guards cytotoxic CD8(+) effector T cells against deviation towards follicular helper T cell lineage","volume":"18","author":"Shan","year":"2017","journal-title":"Nat. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nature24993","article-title":"Runx3 programs CD8(+) T cell residency in non-lymphoid tissues and tumours","volume":"552","author":"Milner","year":"2017","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.immuni.2018.03.028","article-title":"The Transcription Factor Runx3 Establishes Chromatin Accessibility of cis-Regulatory Landscapes that Drive Memory Cytotoxic T Lymphocyte Formation","volume":"48","author":"Wang","year":"2018","journal-title":"Immunity"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3770","DOI":"10.1128\/MCB.00204-09","article-title":"Glycosyltransferase function in core 2-type protein O glycosylation","volume":"29","author":"Stone","year":"2009","journal-title":"Mol. Cell. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Lotem, J., Levanon, D., Negreanu, V., Leshkowitz, D., Friedlander, G., and Groner, Y. (2013). Runx3-mediated transcriptional program in cytotoxic lymphocytes. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080467"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11803","DOI":"10.1074\/jbc.M111.222331","article-title":"RUNX3 maintains the mesenchymal phenotype after termination of the Notch signal","volume":"286","author":"Fu","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1084\/jem.20081242","article-title":"Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs","volume":"206","author":"Pipkin","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Dicken, J., Mildner, A., Leshkowitz, D., Touw, I.P., Hantisteanu, S., Jung, S., and Groner, Y. (2013). Transcriptional reprogramming of CD11b+Esam(hi) dendritic cell identity and function by loss of Runx3. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0077490"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Hantisteanu, S., Dicken, Y., Negreanu, V., Goldenberg, D., Brenner, O., Leshkowitz, D., Lotem, J., Levanon, D., and Groner, Y. (2020). Runx3 prevents spontaneous colitis by directing the differentiation of anti-inflammatory mononuclear phagocytes. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0233044"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1165\/rcmb.2011-0070OC","article-title":"Mouse lung CD103+ and CD11bhigh dendritic cells preferentially induce distinct CD4+ T-cell responses","volume":"46","author":"Furuhashi","year":"2012","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"128","DOI":"10.4110\/in.2014.14.3.128","article-title":"Differential roles of lung dendritic cell subsets against respiratory virus infection","volume":"14","author":"Kim","year":"2014","journal-title":"Immune Netw."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.immuni.2016.10.010","article-title":"Functions of Murine Dendritic Cells","volume":"45","author":"Durai","year":"2016","journal-title":"Immunity"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.alit.2021.01.008","article-title":"Conventional type 2 lung dendritic cells are potent inducers of follicular helper T cells in the asthmatic lung","volume":"70","author":"Sakurai","year":"2021","journal-title":"Allergol. Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"eabi8472","DOI":"10.1126\/sciimmunol.abi8472","article-title":"In vivo reprogramming of pathogenic lung TNFR2(+) cDC2s by IFNbeta inhibits HDM-induced asthma","volume":"6","author":"Mansouri","year":"2021","journal-title":"Sci. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"101495","DOI":"10.1016\/j.trim.2021.101495","article-title":"T helper type (Th1\/Th2) responses to SARS-CoV-2 and influenza A (H1N1) virus: From cytokines produced to immune responses","volume":"70","author":"Molavi","year":"2022","journal-title":"Transpl. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1084\/jem.180.4.1273","article-title":"Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection","volume":"180","author":"Graham","year":"1994","journal-title":"J. Exp. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5230","DOI":"10.1128\/jvi.70.8.5230-5235.1996","article-title":"Interleukin-4 causes delayed virus clearance in influenza virus-infected mice","volume":"70","author":"Moran","year":"1996","journal-title":"J. Virol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1007\/s00277-020-04066-7","article-title":"Signals of T(h)2 immune response from COVID-19 patients requiring intensive care","volume":"99","author":"Roncati","year":"2020","journal-title":"Ann. Hematol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"12564","DOI":"10.1128\/JVI.01559-10","article-title":"Suppression of innate immune pathology by regulatory T cells during Influenza A virus infection of immunodeficient mice","volume":"84","author":"Antunes","year":"2010","journal-title":"J. Virol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1016\/j.cell.2015.08.021","article-title":"A Distinct Function of Regulatory T Cells in Tissue Protection","volume":"162","author":"Arpaia","year":"2015","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1084\/jem.20062456","article-title":"Repression of interleukin-4 in T helper type 1 cells by Runx\/Cbf beta binding to the Il4 silencer","volume":"204","author":"Naoe","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/nature05541","article-title":"Restoration of p53 function leads to tumour regression in vivo","volume":"445","author":"Ventura","year":"2007","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.stem.2009.04.002","article-title":"The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium","volume":"4","author":"Rawlins","year":"2009","journal-title":"Cell Stem Cell"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Hao, Q., Shetty, S., Tucker, T.A., Idell, S., and Tang, H. (2022). Interferon-gamma Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL. Cells, 11.","DOI":"10.3390\/cells11030563"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/8\/4220\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:26:08Z","timestamp":1760106368000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/8\/4220"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,11]]},"references-count":60,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["ijms25084220"],"URL":"https:\/\/doi.org\/10.3390\/ijms25084220","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,11]]}}}