{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T02:24:48Z","timestamp":1769739888791,"version":"3.49.0"},"reference-count":57,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T00:00:00Z","timestamp":1603065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1 NS28752 and RO1 NS33008"],"award-info":[{"award-number":["RO1 NS28752 and RO1 NS33008"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000890","name":"National Multiple Sclerosis Society","doi-asserted-by":"publisher","award":["RG 4001-A6"],"award-info":[{"award-number":["RG 4001-A6"]}],"id":[{"id":"10.13039\/100000890","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The infection of susceptible mice with Theiler\u2019s murine encephalomyelitis virus (TMEV) induces a T cell-mediated demyelinating disease. This system has been studied as a relevant infection model for multiple sclerosis (MS). Therefore, defining the type of T cell responses and their functions is critically important for understanding the relevant pathogenic mechanisms. In this study, we adoptively transferred naive VP2-specific TCR-Tg CD4+ T cells into syngeneic susceptible SJL mice and monitored the development of the disease and the activation and proliferation of CD4+ T cells during the early stages of viral infection. The preexisting VP2-specific naive CD4+ T cells promoted the pathogenesis of the disease in a dose-dependent manner. The transferred VP2-specific CD4+ T cells proliferated rapidly in the CNS starting at 2\u20133 dpi. High levels of FoxP3+CD4+ T cells were found in the CNS early in viral infection (3 dpi) and persisted throughout the infection. Activated VP2-specific FoxP3+CD4+ T cells inhibited the production of IFN-\u03b3, but not IL-17, via the same VP2-specific CD4+ T cells without interfering in proliferation. Thus, the early presence of regulatory T cells in the CNS with viral infection may favor the induction of pathogenic Th17 cells over protective Th1 cells in susceptible mice, thereby establishing the pathogenesis of virus-induced demyelinating disease.<\/jats:p>","DOI":"10.3390\/ijms21207719","type":"journal-article","created":{"date-parts":[[2020,10,19]],"date-time":"2020-10-19T09:36:28Z","timestamp":1603100188000},"page":"7719","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Rapid Expansion of Virus-Specific CD4+ T Cell Types in the CNS of Susceptible Mice Infected with Theiler\u2019s Virus"],"prefix":"10.3390","volume":"21","author":[{"given":"Hyun Seok","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanqiu","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"},{"name":"Michelson Medical Research Foundation, Monrovia, CA 91016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Byung S.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1084\/jem.96.6.517","article-title":"Observations on encephalomyelitis of mice (DA strain)","volume":"96","author":"Daniels","year":"1952","journal-title":"J. Exp. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1128\/iai.11.5.1147-1155.1975","article-title":"Theiler\u2019s virus infection in mice: An unusual biphasic disease process leading to demyelination","volume":"11","author":"Lipton","year":"1975","journal-title":"Infect. Immun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1128\/iai.15.3.903-909.1977","article-title":"Contrasting effects of immunosuppression on Theiler\u2019s virus infection in mice","volume":"15","author":"Lipton","year":"1977","journal-title":"Infect. Immun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1212\/WNL.36.7.964","article-title":"Partial suppression of Theiler\u2019s virus-induced demyelination in vivo by administration of monoclonal antibodies to immune-response gene products (Ia antigens)","volume":"36","author":"Rodriguez","year":"1986","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1099\/0022-1317-68-6-1659","article-title":"The effect of L3T4 T cell depletion on the pathogenesis of Theiler\u2019s murine encephalomyelitis virus infection in CBA mice","volume":"68","author":"Welsh","year":"1987","journal-title":"J. Gen.Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"920","DOI":"10.4049\/jimmunol.136.3.920","article-title":"Characterization of Theiler\u2019s murine encephalomyelitis virus (TMEV)-specific delayed-type hypersensitivity responses in TMEV-induced demyelinating disease: Correlation with clinical signs","volume":"136","author":"Clatch","year":"1986","journal-title":"J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1212\/WNL.34.8.1117","article-title":"Theiler\u2019s virus antigen detected in mouse spinal cord 2 1\/2 years after infection","volume":"34","author":"Lipton","year":"1984","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4252","DOI":"10.1128\/jvi.64.9.4252-4257.1990","article-title":"Genetic mapping of the ability of Theiler\u2019s virus to persist and demyelinate","volume":"64","author":"McAllister","year":"1990","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4497","DOI":"10.4049\/jimmunol.155.9.4497","article-title":"Treatment with bacterial LPS renders genetically resistant C57BL\/6 mice susceptible to Theiler\u2019s virus-induced demyelinating disease","volume":"155","author":"Pullen","year":"1995","journal-title":"J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5606","DOI":"10.1128\/JVI.02442-07","article-title":"Anticapsid immunity level, not viral persistence level, correlates with the progression of Theiler\u2019s virus-induced demyelinating disease in viral P1-transgenic mice","volume":"82","author":"Myoung","year":"2008","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/s12974-016-0597-4","article-title":"Transgenic expression of non-structural genes of Theiler\u2019s virus suppresses initial viral replication and pathogenesis of demyelination","volume":"13","author":"Kang","year":"2016","journal-title":"J. Neuroinflamm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1002\/eji.200535785","article-title":"Initial capsid-specific CD4(+) T cell responses protect against Theiler\u2019s murine encephalomyelitisvirus-induced demyelinating disease","volume":"36","author":"Mohindru","year":"2006","journal-title":"Eur. J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1084\/jem.20082030","article-title":"Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection","volume":"206","author":"Hou","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.jaut.2010.12.005","article-title":"Virus expanded regulatory T cells control disease severity in the Theiler\u2019s virus mouse model of MS","volume":"36","author":"Richards","year":"2011","journal-title":"J. Autoimmun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1128\/JVI.02471-14","article-title":"The level of viral infection of antigen-presenting cells correlates with the level of development of Theiler\u2019s murine encephalomyelitis virus-induced demyelinating disease","volume":"89","author":"Jin","year":"2015","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1002\/glia.20346","article-title":"Induction of chemokine and cytokine genes in astrocytes following infection with Theiler\u2019s murine encephalomyelitis virus is mediated by the Toll-like receptor 3","volume":"53","author":"So","year":"2006","journal-title":"Glia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1002\/glia.20843","article-title":"Theiler\u2019s virus infection induces TLR3-dependent upregulation of TLR2 critical for proinflammatory cytokine production","volume":"57","author":"So","year":"2009","journal-title":"Glia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1128\/JVI.06457-11","article-title":"Melanoma differentiation-associated gene 5 is critical for protection against Theiler\u2019s virus-induced demyelinating disease","volume":"86","author":"Jin","year":"2012","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kim, S.J., Jin, Y.H., and Kim, B.S. (2017). Prostaglandin E2 produced following infection with Theiler\u2019s virus promotes the pathogenesis of demyelinating disease. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176406"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1002\/eji.200838969","article-title":"Prostaglandin E2 enhances Th17 responses via modulation of IL-17 and IFN-gamma production by memory CD4+ T cells","volume":"39","author":"Napolitani","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"21","DOI":"10.4049\/jimmunol.1101029","article-title":"Regulation of immune responses by prostaglandin E2","volume":"188","author":"Kalinski","year":"2012","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"11690","DOI":"10.1128\/JVI.01034-07","article-title":"Differential virus replication, cytokine production, and antigen-presenting function by microglia from susceptible and resistant mice infected with Theiler\u2019s virus","volume":"81","author":"Jin","year":"2007","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1186\/1742-2094-9-217","article-title":"IL-1 signal affects both protection and pathogenesis of virus-induced chronic CNS demyelinating disease","volume":"9","author":"Kim","year":"2012","journal-title":"J. Neuroinflamm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11538","DOI":"10.1128\/JVI.01967-13","article-title":"The role of interleukin-6 in the expression of PD-1 and PDL-1 on central nervous system cells following infection with Theiler\u2019s murine encephalomyelitis virus","volume":"87","author":"Jin","year":"2013","journal-title":"J. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8479","DOI":"10.1128\/JVI.00724-14","article-title":"Interleukin-6 (IL-6) and IL-17 Synergistically Promote Viral Persistence by Inhibiting Cellular Apoptosis and Cytotoxic T Cell Function","volume":"88","author":"Hou","year":"2014","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"331","DOI":"10.5114\/ceji.2018.80053","article-title":"The immunological implication of the new vitamin D metabolism","volume":"43","author":"Bivona","year":"2018","journal-title":"Cent. Eur. J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4091","DOI":"10.1073\/pnas.0408679102","article-title":"Foxp3+ CD25- CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion","volume":"102","author":"Zelenay","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1126\/science.1145697","article-title":"Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid","volume":"317","author":"Mucida","year":"2007","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1084\/jem.20070590","article-title":"A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism","volume":"204","author":"Coombes","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Zhao, J., Zhao, J., and Perlman, S. (2014). Virus-specific regulatory T cells ameliorate encephalitis by repressing effector T cell functions from priming to effector stages. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004279"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1186\/1742-2094-8-178","article-title":"TLR3 signaling is either protective or pathogenic for the development of Theiler\u2019s virus-induced demyelinating disease depending on the time of viral infection","volume":"8","author":"Jin","year":"2011","journal-title":"J. Neuroinflamm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.jneuroim.2003.12.025","article-title":"The scope and activation mechanisms of chemokine gene expression in primary astrocytes following infection with Theiler\u2019s virus","volume":"149","author":"Palma","year":"2004","journal-title":"J. Neuroimmunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/glia.20450","article-title":"Distinct roles of protein kinase R and toll-like receptor 3 in the activation of astrocytes by viral stimuli","volume":"55","author":"Carpentier","year":"2007","journal-title":"Glia"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1186\/s12974-015-0462-x","article-title":"Interferon-stimulated genes-essential antiviral effectors implicated in resistance to Theiler\u2019s virus-induced demyelinating disease","volume":"12","author":"Li","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1093\/intimm\/8.7.1001","article-title":"The level of tumor necrosis factor-alpha producing cells in the spinal cord correlates with the degree of Theiler\u2019s murine encephalomyelitis virus-induced demyelinating disease","volume":"8","author":"Inoue","year":"1996","journal-title":"Int. Immun."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Hou, W., So, E.Y., and Kim, B.S. (2007). Role of dendritic cells in differential susceptibility to viral demyelinating disease. PLoS Pathog., 3.","DOI":"10.1371\/journal.ppat.0030124"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jneuroim.2010.05.028","article-title":"Type I interferon signals control Theiler\u2019s virus infection site, cellular infiltration and T cell stimulation in the CNS","volume":"226","author":"Jin","year":"2010","journal-title":"J. Neuroimmunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1126\/science.80.2066.122.b","article-title":"Spontaneous encephalomyelitis of mice\u2014A new virus disease","volume":"80","author":"Theiler","year":"1934","journal-title":"Science"},{"key":"ref_39","first-page":"455","article-title":"A new model of persistent viral infection with primary demyelination","volume":"18","author":"Lipton","year":"1977","journal-title":"Neurol. Neurocir. Psiquiatr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/j.1600-065X.1989.tb00543.x","article-title":"Regulation of T-cell activation: Differences among T-cell subsets","volume":"111","author":"Gajewski","year":"1989","journal-title":"Immunol. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.coi.2006.03.017","article-title":"Expanding the effector CD4 T-cell repertoire: The Th17 lineage","volume":"18","author":"Harrington","year":"2006","journal-title":"Curr. Opin. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Nawijn, M.C., Motta, A.C., Gras, R., Shirinbak, S., Maazi, H., and van Oosterhout, A.J. (2013). TLR-2 activation induces regulatory T cells and long-term suppression of asthma manifestations in mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0055307"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Yamazaki, S., Okada, K., Maruyama, A., Matsumoto, M., Yagita, H., and Seya, T. (2011). TLR2-dependent induction of IL-10 and Foxp3+ CD25+ CD4+ regulatory T cells prevents effective anti-tumor immunity induced by Pam2 lipopeptides in vivo. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0018833"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s12974-014-0180-9","article-title":"Limited role of regulatory T cells during acute Theiler virus-induced encephalitis in resistant C57BL\/6 mice","volume":"11","author":"Prajeeth","year":"2014","journal-title":"J. Neuroinflamm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1084\/jem.20030152","article-title":"Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3","volume":"198","author":"Chen","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1172\/JCI19441","article-title":"Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells","volume":"112","author":"Walker","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.clim.2008.07.029","article-title":"Intrahepatic regulatory T cells are phenotypically distinct from their peripheral counterparts in chronic HBV patients","volume":"129","author":"Stoop","year":"2008","journal-title":"Clin. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.4049\/jimmunol.182.3.1689","article-title":"Phenotypic and functional analysis of CD4+ CD25- Foxp3+ T cells in patients with systemic lupus erythematosus","volume":"182","author":"Bonelli","year":"2009","journal-title":"J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3137","DOI":"10.4049\/jimmunol.181.5.3137","article-title":"Reprogrammed FoxP3+ T regulatory cells become IL-17+ antigen-specific autoimmune effectors in vitro and in vivo","volume":"181","author":"Radhakrishnan","year":"2008","journal-title":"J. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/nm.3432","article-title":"Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis","volume":"20","author":"Komatsu","year":"2014","journal-title":"Nat. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1111\/imr.12085","article-title":"Role of regulatory T cells during virus infection","volume":"255","author":"Sehrawat","year":"2013","journal-title":"Immunol. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4123","DOI":"10.4049\/jimmunol.172.7.4123","article-title":"CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions","volume":"172","author":"Suvas","year":"2004","journal-title":"J. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"4391","DOI":"10.4049\/jimmunol.0903918","article-title":"Regulatory T cells inhibit T cell proliferation and decrease demyelination in mice chronically infected with a coronavirus","volume":"184","author":"Trandem","year":"2010","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1189\/jlb.1006610","article-title":"Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17","volume":"81","author":"Nakae","year":"2007","journal-title":"J. Leukoc. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"583","DOI":"10.4049\/jimmunol.165.1.583","article-title":"Clonal expansion of infiltrating T cells in the spinal cords of SJL\/J mice infected with Theiler\u2019s virus","volume":"165","author":"Kang","year":"2000","journal-title":"J. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6577","DOI":"10.1128\/JVI.76.13.6577-6585.2002","article-title":"The majority of infiltrating CD8+ T cells in the central nervous system of susceptible SJL\/J mice infected with Theiler\u2019s virus are virus specific and fully functional","volume":"76","author":"Kang","year":"2002","journal-title":"J. Virol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3955","DOI":"10.4049\/jimmunol.175.6.3955","article-title":"Gender bias in Theiler\u2019s virus-induced demyelinating disease correlates with the level of antiviral immune responses","volume":"175","author":"Fuller","year":"2005","journal-title":"J. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/20\/7719\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:23:38Z","timestamp":1760178218000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/20\/7719"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,19]]},"references-count":57,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["ijms21207719"],"URL":"https:\/\/doi.org\/10.3390\/ijms21207719","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,19]]}}}