{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T10:36:22Z","timestamp":1782729382026,"version":"3.54.5"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2012,4,1]],"date-time":"2012-04-01T00:00:00Z","timestamp":1333238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Regulatory T cells (Tregs) are important for the attenuation of immune reactions. During viral CNS infections, however, an indiscriminate maintenance of CNS immune privilege through Treg-mediated negative regulation could prevent autoimmune sequelae but impair the control of viral replication. We analyzed in this study the impact of Tregs on the development of acute viral encephalomyelitis, T cell-mediated antiviral protection, and prevention of CNS autoimmunity following intranasal infection with the gliatropic mouse hepatitis virus strain A59. To assess the contribution of Tregs in vivo, we specifically depleted CD4+Foxp3+ T cells in a diphtheria toxin-dependent manner. We found that depletion of Tregs had no impact on viral distribution and clearance and did not significantly alter virus-specific CD4+ and CD8+ T cell responses. However, Treg depletion led to a more severe CNS inflammation associated with neuronal damage. Dissection of the underlying immunopathological mechanisms revealed the elaborate Treg-dependent regulation of self-reactive CD4+ T cell proliferation within the CNS-draining lymph node and downtuning of CXCR3 expression on T cells. Taken together, these results suggest that Tregs preserve CNS immune privilege through selective control of CNS-specific Th cells while keeping protective antiviral immunity fully operative.<\/jats:p>","DOI":"10.4049\/jimmunol.1102422","type":"journal-article","created":{"date-parts":[[2012,3,10]],"date-time":"2012-03-10T19:03:05Z","timestamp":1331406185000},"page":"3678-3685","source":"Crossref","is-referenced-by-count":39,"title":["Regulatory T Cells Selectively Preserve Immune Privilege of Self-Antigens during Viral Central Nervous System Infection"],"prefix":"10.1093","volume":"188","author":[{"given":"Luisa","family":"Cervantes-Barrag\u00e1n","sequence":"first","affiliation":[{"name":"Institute of Immunobiology, Kantonal Hospital St. Gallen , 9007 St. Gallen ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Firner","sequence":"additional","affiliation":[{"name":"Institute of Immunobiology, Kantonal Hospital St. Gallen , 9007 St. Gallen ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Bechmann","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, University of Leipzig , Leipzig 04103 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ari","family":"Waisman","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine, University of Mainz , Mainz 55131 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Lahl","sequence":"additional","affiliation":[{"name":"Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine , Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Sparwasser","sequence":"additional","affiliation":[{"name":"Institute of Infection Immunology, TWINCORE, Hannover Medical School , Hannover 30625 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Thiel","sequence":"additional","affiliation":[{"name":"Institute of Immunobiology, Kantonal Hospital St. Gallen , 9007 St. Gallen ,","place":["Switzerland"]},{"name":"Vetsuisse Faculty, University of Z\u00fcrich , 8057 Z\u00fcrich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burkhard","family":"Ludewig","sequence":"additional","affiliation":[{"name":"Institute of Immunobiology, Kantonal Hospital St. Gallen , 9007 St. Gallen ,","place":["Switzerland"]},{"name":"Vetsuisse Faculty, University of Z\u00fcrich , 8057 Z\u00fcrich ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,4,15]]},"reference":[{"key":"2025032410040463300_r1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S1474-4422(05)70023-5","article-title":"Infectious causes of multiple sclerosis","volume":"4","author":"Gilden","year":"2005","journal-title":"Lancet Neurol."},{"key":"2025032410040463300_r2","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/nri2527","article-title":"Antiviral immune responses: triggers of or triggered by autoimmunity?","volume":"9","author":"M\u00fcnz","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"2025032410040463300_r3","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1002\/ana.21978","article-title":"Primary infection with the Epstein-Barr virus and risk of multiple sclerosis","volume":"67","author":"Levin","year":"2010","journal-title":"Ann. Neurol."},{"key":"2025032410040463300_r4","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1038\/nm1297-1394","article-title":"Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA","volume":"3","author":"Soldan","year":"1997","journal-title":"Nat. Med."},{"key":"2025032410040463300_r5","doi-asserted-by":"crossref","first-page":"8913","DOI":"10.1128\/JVI.74.19.8913-8921.2000","article-title":"Neuroinvasion by human respiratory coronaviruses","volume":"74","author":"Arbour","year":"2000","journal-title":"J. Virol."},{"key":"2025032410040463300_r6","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/0042-6822(92)90220-J","article-title":"Human coronavirus gene expression in the brains of multiple sclerosis patients","volume":"191","author":"Stewart","year":"1992","journal-title":"Virology"},{"key":"2025032410040463300_r7","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1093\/brain\/awl067","article-title":"Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis","volume":"129","author":"L\u00fcnemann","year":"2006","journal-title":"Brain"},{"key":"2025032410040463300_r8","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.clim.2007.02.002","article-title":"Long-term human coronavirus-myelin cross-reactive T-cell clones derived from multiple sclerosis patients","volume":"123","author":"Boucher","year":"2007","journal-title":"Clin. Immunol."},{"key":"2025032410040463300_r9","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1038\/nm1097-1133","article-title":"Persistent infection with Theiler\u2019s virus leads to CNS autoimmunity via epitope spreading","volume":"3","author":"Miller","year":"1997","journal-title":"Nat. Med."},{"key":"2025032410040463300_r10","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.it.2006.11.004","article-title":"What is immune privilege (not)?","volume":"28","author":"Galea","year":"2007","journal-title":"Trends Immunol."},{"key":"2025032410040463300_r11","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1111\/j.1600-065X.2011.01011.x","article-title":"Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28\/\u200aB7 family","volume":"241","author":"Bour-Jordan","year":"2011","journal-title":"Immunol. Rev."},{"key":"2025032410040463300_r12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molimm.2010.09.010","article-title":"Regulatory B cells: evidence, developmental origin and population diversity","volume":"48","author":"Vitale","year":"2010","journal-title":"Mol. Immunol."},{"key":"2025032410040463300_r13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/ni.1818","article-title":"Regulatory T cells exert checks and balances on self tolerance and autoimmunity","volume":"11","author":"Wing","year":"2010","journal-title":"Nat. Immunol."},{"key":"2025032410040463300_r14","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/nri2343","article-title":"How regulatory T cells work","volume":"8","author":"Vignali","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"2025032410040463300_r15","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/ni1455","article-title":"Foxp3 in control of the regulatory T cell lineage","volume":"8","author":"Zheng","year":"2007","journal-title":"Nat. Immunol."},{"key":"2025032410040463300_r16","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.immuni.2009.04.010","article-title":"Mechanisms of foxp3+ T regulatory cell-mediated suppression","volume":"30","author":"Shevach","year":"2009","journal-title":"Immunity"},{"key":"2025032410040463300_r17","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.molmed.2009.12.003","article-title":"Disturbed regulatory T cell homeostasis in multiple sclerosis","volume":"16","author":"Venken","year":"2010","journal-title":"Trends Mol. Med."},{"key":"2025032410040463300_r18","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/j.1600-065X.2006.00428.x","article-title":"Immune privilege induced by regulatory T cells in transplantation tolerance","volume":"213","author":"Cobbold","year":"2006","journal-title":"Immunol. Rev."},{"key":"2025032410040463300_r19","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1126\/science.1155209","article-title":"Coordination of early protective immunity to viral infection by regulatory T cells","volume":"320","author":"Lund","year":"2008","journal-title":"Science"},{"key":"2025032410040463300_r20","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.4049\/jimmunol.1000423","article-title":"Foxp3+ CD4 regulatory T cells limit pulmonary immunopathology by modulating the CD8 T cell response during respiratory syncytial virus infection","volume":"185","author":"Fulton","year":"2010","journal-title":"J. Immunol."},{"key":"2025032410040463300_r21","doi-asserted-by":"crossref","first-page":"e1000406","DOI":"10.1371\/journal.ppat.1000406","article-title":"Regulatory T cells suppress antiviral immune responses and increase viral loads during acute infection with a lymphotropic retrovirus","volume":"5","author":"Zelinskyy","year":"2009","journal-title":"PLoS Pathog."},{"key":"2025032410040463300_r22","doi-asserted-by":"crossref","first-page":"3199","DOI":"10.1182\/blood-2009-03-208736","article-title":"The regulatory T-cell response during acute retroviral infection is locally defined and controls the magnitude and duration of the virus-specific cytotoxic T-cell response","volume":"114","author":"Zelinskyy","year":"2009","journal-title":"Blood"},{"key":"2025032410040463300_r23","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrmicro1343","article-title":"Coronavirus infection of the central nervous system: host-virus stand-off","volume":"4","author":"Bergmann","year":"2006","journal-title":"Nat. Rev. Microbiol."},{"key":"2025032410040463300_r24","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1084\/jem.20061852","article-title":"Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease","volume":"204","author":"Lahl","year":"2007","journal-title":"J. Exp. Med."},{"key":"2025032410040463300_r25","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1084\/jem.20021603","article-title":"Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis","volume":"197","author":"Bettelli","year":"2003","journal-title":"J. Exp. Med."},{"key":"2025032410040463300_r26","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.4049\/jimmunol.182.2.1099","article-title":"Type I IFN-mediated protection of macrophages and dendritic cells secures control of murine coronavirus infection","volume":"182","author":"Cervantes-Barrag\u00e1n","year":"2009","journal-title":"J. Immunol."},{"key":"2025032410040463300_r27","doi-asserted-by":"crossref","first-page":"e109","DOI":"10.1371\/journal.ppat.0030109","article-title":"Identification of coronavirus non-structural protein 1 as a major pathogenicity factor-implications for the rational design of live attenuated coronavirus vaccines","volume":"3","author":"Z\u00fcst","year":"2007","journal-title":"PLoS Pathog."},{"key":"2025032410040463300_r28","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.it.2006.11.007","article-title":"What is the blood-brain barrier (not)?","volume":"28","author":"Bechmann","year":"2007","journal-title":"Trends Immunol."},{"key":"2025032410040463300_r29","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1006\/viro.1996.0415","article-title":"Differential antigen recognition by T cells from the spleen and central nervous system of coronavirus-infected mice","volume":"222","author":"Castro","year":"1996","journal-title":"Virology"},{"key":"2025032410040463300_r30","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1006\/viro.1995.1140","article-title":"Identification of a CD4+ T cell epitope within the M protein of a neurotropic coronavirus","volume":"208","author":"Xue","year":"1995","journal-title":"Virology"},{"key":"2025032410040463300_r31","first-page":"1379","article-title":"X-linked lymphoreticular disease in the scurfy (sf) mutant mouse","volume":"138","author":"Godfrey","year":"1991","journal-title":"Am. J. Pathol."},{"key":"2025032410040463300_r32","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1182\/blood-2006-05-023770","article-title":"Control of coronavirus infection through plasmacytoid dendritic-cell-derived type I interferon","volume":"109","author":"Cervantes-Barragan","year":"2007","journal-title":"Blood"},{"key":"2025032410040463300_r33","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1038\/ni.1716","article-title":"C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE","volume":"10","author":"Reboldi","year":"2009","journal-title":"Nat. Immunol."},{"key":"2025032410040463300_r34","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.4049\/jimmunol.165.5.2327","article-title":"The T cell chemoattractant IFN-inducible protein 10 is essential in host defense against viral-induced neurologic disease","volume":"165","author":"Liu","year":"2000","journal-title":"J. Immunol."},{"key":"2025032410040463300_r35","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1080\/08916930902810708","article-title":"CXCL10 and trafficking of virus-specific T cells during coronavirus-induced demyelination","volume":"42","author":"Stiles","year":"2009","journal-title":"Autoimmunity"},{"key":"2025032410040463300_r36","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/nm1197","article-title":"Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis","volume":"11","author":"Greter","year":"2005","journal-title":"Nat. Med."},{"key":"2025032410040463300_r37","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1111\/j.1600-065X.2006.00432.x","article-title":"Immune privilege in sites of chronic infection: Leishmania and regulatory T cells","volume":"213","author":"Peters","year":"2006","journal-title":"Immunol. Rev."},{"key":"2025032410040463300_r38","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1038\/nature01152","article-title":"CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity","volume":"420","author":"Belkaid","year":"2002","journal-title":"Nature"},{"key":"2025032410040463300_r39","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1073\/pnas.1015148108","article-title":"Transient depletion of regulatory T cells in transgenic mice reactivates virus-specific CD8+ T cells and reduces chronic retroviral set points","volume":"108","author":"Dietze","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032410040463300_r40","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":"2025032410040463300_r41","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.virol.2008.12.014","article-title":"Role of regulatory T cells in coronavirus-induced acute encephalitis","volume":"385","author":"Anghelina","year":"2009","journal-title":"Virology"},{"key":"2025032410040463300_r42","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1084\/jem.20110236","article-title":"IFN-\u03b3- and IL-10-expressing virus epitope-specific Foxp3(+) T reg cells in the central nervous system during encephalomyelitis","volume":"208","author":"Zhao","year":"2011","journal-title":"J. Exp. Med."},{"key":"2025032410040463300_r43","doi-asserted-by":"crossref","first-page":"4895","DOI":"10.4049\/jimmunol.0901459","article-title":"Dominant role of antigen dose in CD4+Foxp3+ regulatory T cell induction and expansion","volume":"183","author":"Turner","year":"2009","journal-title":"J. Immunol."},{"key":"2025032410040463300_r44","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.4049\/jimmunol.0803721","article-title":"IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells","volume":"183","author":"Goodman","year":"2009","journal-title":"J. Immunol."},{"key":"2025032410040463300_r45","doi-asserted-by":"crossref","first-page":"3336","DOI":"10.4049\/jimmunol.1001455","article-title":"Stat3 phosphorylation mediates resistance of primary human T cells to regulatory T cell suppression","volume":"186","author":"Goodman","year":"2011","journal-title":"J. Immunol."},{"key":"2025032410040463300_r46","doi-asserted-by":"crossref","first-page":"12325","DOI":"10.1128\/JVI.02082-08","article-title":"Mouse hepatitis virus liver pathology is dependent on ADP-ribose-1\u2033-phosphatase, a viral function conserved in the alpha-like supergroup","volume":"82","author":"Eriksson","year":"2008","journal-title":"J. Virol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/188\/8\/3678\/62481148\/1102422.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/188\/8\/3678\/62481148\/1102422.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T20:42:56Z","timestamp":1743108176000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/188\/8\/3678\/7981575"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,4]]},"references-count":46,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2012,4,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1102422","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2012,4]]},"published":{"date-parts":[[2012,4]]}}}