{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:35:26Z","timestamp":1792625726794,"version":"4.5.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T00:00:00Z","timestamp":1620345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006321","name":"National Institutes of Natural Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006321","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006321","name":"National Institutes of Natural Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006321","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Viral encephalitis is the most common cause of encephalitis. It is responsible for high morbidity rates, permanent neurological sequelae, and even high mortality rates. The host immune response plays a critical role in preventing or clearing invading pathogens, especially when effective antiviral treatment is lacking. However, due to blockade of the blood-brain barrier, it remains unclear how peripheral immune cells contribute to the fight against intracerebral viruses. Here, we report that peripheral injection of an antibody against human Tim-3, an immune checkpoint inhibitor widely expressed on immune cells, markedly attenuated vesicular stomatitis virus (VSV) encephalitis, marked by decreased mortality and improved neuroethology in mice. Peripheral injection of Tim-3 antibody enhanced the recruitment of immune cells to the brain, increased the expression of major histocompatibility complex-I (MHC-I) on macrophages, and as a result, promoted the activation of VSV-specific CD8<jats:sup>+<\/jats:sup> T cells. Depletion of macrophages abolished the peripheral injection-mediated protection against VSV encephalitis. Notably, for the first time, we found a novel post-translational modification of MHC-I by Tim-3, wherein, by enhancing the expression of MARCH9, Tim-3 promoted the proteasome-dependent degradation of MHC-I <jats:italic>via<\/jats:italic> K48-linked ubiquitination in macrophages. These results provide insights into the immune response against intracranial infections; thus, manipulating the peripheral immune cells with Tim-3 antibody to fight viruses in the brain may have potential applications for combating viral encephalitis.<\/jats:p>","DOI":"10.3389\/fimmu.2021.667478","type":"journal-article","created":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T14:48:11Z","timestamp":1620398891000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Peripheral Injection of Tim-3 Antibody Attenuates VSV Encephalitis by Enhancing MHC-I Presentation"],"prefix":"10.3389","volume":"12","author":[{"given":"Ge","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunmei","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiding","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuaijie","family":"Dou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongliang","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenfang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beifen","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renxi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gencheng","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,5,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)62707-5","article-title":"Current Status of Rabies and Prospects for Elimination","volume":"384","author":"Fooks","year":"2014","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1478-7954-9-1","article-title":"Measuring the Burden of Arboviral Diseases: The Spectrum of Morbidity and Mortality From Four Prevalent Infections","volume":"9","author":"Labeaud","year":"2011","journal-title":"Popul Health Metr"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32526-1","article-title":"Acute Encephalitis in Immunocompetent Adults","volume":"393","author":"Venkatesan","year":"2019","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2174\/187152412803760582","article-title":"Viral Encephalitis: Current Treatments and Future Perspectives","volume":"12","author":"Domingues","year":"2012","journal-title":"Cent Nerv Syst Agents Med Chem"},{"key":"B5","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.bbi.2018.09.006","article-title":"Microglia Have a Protective Role in Viral Encephalitis-Induced Seizure Development and Hippocampal Damage","volume":"74","author":"Waltl","year":"2018","journal-title":"Brain Behav Immun"},{"key":"B6","doi-asserted-by":"publisher","first-page":"a020412","DOI":"10.1101\/cshperspect.a020412","article-title":"The Blood-Brain Barrier","volume":"7","author":"Daneman","year":"2015","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1159\/000486200","article-title":"Extravascular Cd3+ T Cells in Brains of Alzheimer Disease Patients Correlate With Tau But Not With Amyloid Pathology: An Immunohistochemical Study","volume":"18","author":"Merlini","year":"2018","journal-title":"Neurodegener Dis"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3554","article-title":"The Microglial Sensome Revealed by Direct RNA Sequencing","volume":"16","author":"Hickman","year":"2013","journal-title":"Nat Neurosci"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1126\/science.1194637","article-title":"Fate Mapping Analysis Reveals That Adult Microglia Derive From Primitive Macrophages","volume":"330","author":"Ginhoux","year":"2010","journal-title":"Science"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nature13989","article-title":"Tissue-Resident Macrophages Originate From Yolk-Sac-Derived Erythro-Myeloid Progenitors","volume":"518","author":"Gomez Perdiguero","year":"2015","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2016.09.006","article-title":"Microglia Depletion in Early Life Programs Persistent Changes in Social, Mood-Related, and Locomotor Behavior in Male and Female Rats","volume":"316","author":"Nelson","year":"2017","journal-title":"Behav Brain Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1126\/science.1110647","article-title":"Resting Microglial Cells are Highly Dynamic Surveillants of Brain Parenchyma In Vivo","volume":"308","author":"Nimmerjahn","year":"2005","journal-title":"Science"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1126\/science.1202529","article-title":"Synaptic Pruning by Microglia is Necessary for Normal Brain Development","volume":"333","author":"Paolicelli","year":"2011","journal-title":"Science"},{"key":"B14","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1016\/j.neuron.2012.03.026","article-title":"Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner","volume":"74","author":"Schafer","year":"2012","journal-title":"Neuron"},{"key":"B15","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1038\/s41590-018-0159-2","article-title":"Publisher Correction: Macrophages: Damage Control","volume":"19","author":"Fehervari","year":"2018","journal-title":"Nat Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.17.7903-7910.2000","article-title":"Role of Viral Persistence in Retaining CD8(+) T Cells Within the Central Nervous System","volume":"74","author":"Marten","year":"2000","journal-title":"J Virol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.6.3204","article-title":"Perforin-Mediated Effector Function Within the Central Nervous System Requires IFN-gamma-mediated MHC Up-Regulation","volume":"170","author":"Bergmann","year":"2003","journal-title":"J Immunol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1002\/embj.201386609","article-title":"The Resolution of Neuroinflammation in Neurodegeneration: Leukocyte Recruitment Via the Choroid Plexus","volume":"33","author":"Schwartz","year":"2014","journal-title":"EMBO J"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4022","article-title":"PD-1 Immune Checkpoint Blockade Reduces Pathology and Improves Memory in Mouse Models of Alzheimer\u2019s Disease","volume":"22","author":"Baruch","year":"2016","journal-title":"Nat Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/s41467-019-08352-5","article-title":"Pd-1\/Pd-L1 Checkpoint Blockade Harnesses Monocyte-Derived Macrophages to Combat Cognitive Impairment in a Tauopathy Mouse Model","volume":"10","author":"Rosenzweig","year":"2019","journal-title":"Nat Commun"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081398","article-title":"Tim-3 Expression Defines a Novel Population of Dysfunctional T Cells With Highly Elevated Frequencies in Progressive HIV-1 Infection","volume":"205","author":"Jones","year":"2008","journal-title":"J Exp Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/415536a","article-title":"Th1-specific Cell Surface Protein Tim-3 Regulates Macrophage Activation and Severity of an Autoimmune Disease","volume":"415","author":"Monney","year":"2002","journal-title":"Nature"},{"key":"B23","doi-asserted-by":"publisher","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":"B24","doi-asserted-by":"publisher","first-page":"e1211219","DOI":"10.1080\/2162402X.2016.1211219","article-title":"Tim-3 Promotes Tumor-Promoting M2 Macrophage Polarization by Binding to STAT1 and Suppressing the STAT1-miR-155 Signaling Axis","volume":"5","author":"Jiang","year":"2016","journal-title":"Oncoimmunology"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.01.011","article-title":"Induction of Siglec-G by RNA Viruses Inhibits the Innate Immune Response by Promoting RIG-I Degradation","volume":"152","author":"Chen","year":"2013","journal-title":"Cell"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1740-17.2018","article-title":"Long-Term Neuroinflammation Induced by Influenza A Virus Infection and the Impact on Hippocampal Neuron Morphology and Function","volume":"38","author":"Hosseini","year":"2018","journal-title":"J Neurosci"},{"key":"B27","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.bbi.2017.09.006","article-title":"Peripheral Immune Cells Infiltrate Into Sites of Secondary Neurodegeneration After Ischemic Stroke","volume":"67","author":"Jones","year":"2018","journal-title":"Brain Behav Immun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02304","article-title":"Optimized Protocol for the Detection of Multifunctional Epitope-Specific Cd4(+) T Cells Combining Mhc-Ii Tetramer and Intracellular Cytokine Staining Technologies","volume":"10","author":"Pastore","year":"2019","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2923","article-title":"Heterogeneity of CNS Myeloid Cells and Their Roles in Neurodegeneration","volume":"14","author":"Prinz","year":"2011","journal-title":"Nat Neurosci"},{"key":"B30","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.jneuroim.2013.12.002","article-title":"Role of Peripheral Immune Response in Microglia Activation and Regulation of Brain Chemokine and Proinflammatory Cytokine Responses Induced During VSV Encephalitis","volume":"267","author":"Steel","year":"2014","journal-title":"J Neuroimmunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2015.03.010","article-title":"Viral Immune Evasion: Lessons in MHC Class I Antigen Presentation","volume":"27","author":"van de Weijer","year":"2015","journal-title":"Semin Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-9450-2_18","article-title":"Monitoring MHC Ubiquitination by MARCH Ubiquitin Ligases","volume":"1988","author":"Gatti","year":"2019","journal-title":"Methods Mol Biol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1038\/s41467-018-03008-2","article-title":"Klf4 Glutamylation is Required for Cell Reprogramming and Early Embryonic Development in Mice","volume":"9","author":"Ye","year":"2018","journal-title":"Nat Commun"},{"key":"B34","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.celrep.2018.09.003","article-title":"Type I Interferon Receptor Signaling of Neurons and Astrocytes Regulates Microglia Activation During Viral Encephalitis","volume":"25","author":"Chhatbar","year":"2018","journal-title":"Cell Rep"},{"key":"B35","doi-asserted-by":"publisher","first-page":"e1004319","DOI":"10.1371\/journal.ppat.1004319","article-title":"Distinct Dictation of Japanese Encephalitis Virus-Induced Neuroinflammation and Lethality Via Triggering TLR3 and TLR4 Signal Pathways","volume":"10","author":"Han","year":"2014","journal-title":"PloS Pathog"},{"key":"B36","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1111\/imm.12626","article-title":"CCL2, But Not its Receptor, is Essential to Restrict Immune Privileged Central Nervous System-Invasion of Japanese Encephalitis Virus Via Regulating Accumulation of CD11b(+) Ly-6C(hi) Monocytes","volume":"149","author":"Kim","year":"2016","journal-title":"Immunology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1038\/nrneurol.2018.30","article-title":"Japanese Encephalitis - the Prospects for New Treatments","volume":"14","author":"Turtle","year":"2018","journal-title":"Nat Rev Neurol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2020.09.015","article-title":"Influenza Vaccine Combined With Moderate-Dose PD1 Blockade Reduces Amyloid-Beta Accumulation and Improves Cognition in APP\/PS1 Mice","volume":"91","author":"Xing","year":"2021","journal-title":"Brain Behav Immun"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1172\/JCI92931","article-title":"Herpes Simplex Virus-1 Evasion of CD8+ T Cell Accumulation Contributes to Viral Encephalitis","volume":"127","author":"Koyanagi","year":"2017","journal-title":"J Clin Invest"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiz512","article-title":"Tim-3 Promotes Listeria Monocytogenes Immune Evasion by Suppressing Major Histocompatibility Complex Class I","volume":"221","author":"Wang","year":"2020","journal-title":"J Infect Dis"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/biof.1285","article-title":"Cita\/Nlrc5: A Critical Transcriptional Regulator of MHC Class I Gene Expression","volume":"42","author":"Downs","year":"2016","journal-title":"Biofactors"},{"key":"B42","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/s41598-017-18464-x","article-title":"MHC Class I Expression in Intestinal Cells is Reduced by Rotavirus Infection and Increased in Bystander Cells Lacking Rotavirus Antigen","volume":"8","author":"Holloway","year":"2018","journal-title":"Sci Rep"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1008684107","article-title":"NLR Family Member NLRC5 is a Transcriptional Regulator of MHC Class I Genes","volume":"107","author":"Meissner","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B44","doi-asserted-by":"publisher","first-page":"e0174","DOI":"10.1199\/tab.0174","article-title":"The Ubiquitination Machinery of the Ubiquitin System","volume":"12","author":"Callis","year":"2014","journal-title":"Arabidopsis Book"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1084\/jem.20151531","article-title":"Ubiquitin in the Activation and Attenuation of Innate Antiviral Immunity","volume":"213","author":"Heaton","year":"2016","journal-title":"J Exp Med"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02183-15","article-title":"The Missing Link in Epstein-Barr Virus Immune Evasion: The BDLF3 Gene Induces Ubiquitination and Downregulation of Major Histocompatibility Complex Class I (Mhc-I) and MHC-II","volume":"90","author":"Quinn","year":"2016","journal-title":"J Virol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/35069118","article-title":"Crystal Structure of the B7-1\/CTLA-4 Complex That Inhibits Human Immune Responses","volume":"410","author":"Stamper","year":"2001","journal-title":"Nature"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-14-0039","article-title":"Tim-3: An Emerging Target in the Cancer Immunotherapy Landscape","volume":"2","author":"Anderson","year":"2014","journal-title":"Cancer Immunol Res"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202661","article-title":"T Cell Ig Mucin-3 Promotes Homeostasis of Sepsis by Negatively Regulating the TLR Response","volume":"190","author":"Yang","year":"2013","journal-title":"J Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.667478\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T14:48:13Z","timestamp":1620398893000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.667478\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,7]]},"references-count":49,"alternative-id":["10.3389\/fimmu.2021.667478"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.667478","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,7]]},"article-number":"667478"}}