{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T09:16:07Z","timestamp":1789809367229,"version":"4.0.1"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2012,10,1]],"date-time":"2012-10-01T00:00:00Z","timestamp":1349049600000},"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":[[2012,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Virus-specific CD4+ T cells play a central role in control of viral pathogens including JC polyoma virus (JCV) infection. JCV is a ubiquitous small DNA virus that leads to persistent infection of humans with no clinical consequences. However, under circumstances of immunocompromise, it is able to cause an opportunistic and often fatal infection of the brain called progressive multifocal leukoencephalopathy (PML). PML has emerged as a serious adverse event in multiple sclerosis patients treated with the anti\u2013VLA-4 mAb natalizumab, which selectively inhibits cell migration across the blood\u2013brain barrier and the gut\u2019s vascular endothelium thus compromising immune surveillance in the CNS and gut. In a multiple sclerosis patient who developed PML under natalizumab treatment and a vigorous immune response against JCV after Ab washout, we had the unique opportunity to characterize in detail JCV-specific CD4+ T cell clones from the infected tissue during acute viral infection. The in-depth analysis of 14 brain-infiltrating, JCV-specific CD4+ T cell clones demonstrated that these cells use an unexpectedly broad spectrum of different strategies to mount an efficient JCV-specific immune response including TCR bias, HLA cross-restriction that increases avidity and influences in vivo expansion, and a combination of Th1 and Th1-2 functional phenotypes. The level of combinatorial diversity in TCR\u2013 and HLA\u2013peptide interactions used by brain-infiltrating, JCV-specific CD4+ T cells has not, to our knowledge, been reported before in humans for other viral infections and confirms the exceptional plasticity that characterizes virus-specific immune responses.<\/jats:p>","DOI":"10.4049\/jimmunol.1201612","type":"journal-article","created":{"date-parts":[[2012,9,1]],"date-time":"2012-09-01T16:43:04Z","timestamp":1346517784000},"page":"3618-3630","source":"Crossref","is-referenced-by-count":32,"title":["TCR Bias and HLA Cross-Restriction Are Strategies of Human Brain-Infiltrating JC Virus-Specific CD4+ T Cells during Viral Infection"],"prefix":"10.1093","volume":"189","author":[{"given":"Sara","family":"Yousef","sequence":"first","affiliation":[{"name":"Institute for Neuroimmunology and Clinical Multiple Sclerosis Research, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf , 20251 Hamburg,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Planas","sequence":"additional","affiliation":[{"name":"Institute for Neuroimmunology and Clinical Multiple Sclerosis Research, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf , 20251 Hamburg,","place":["Germany"]},{"name":"Department of Neuroimmunology and Multiple Sclerosis Research, Neurology Clinic, University Hospital, University of Z\u00fcrich , 8091 Z\u00fcrich,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karima","family":"Chakroun","sequence":"additional","affiliation":[{"name":"Institute for Neuroimmunology and Clinical Multiple Sclerosis Research, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf , 20251 Hamburg,","place":["Germany"]},{"name":"Institute of Neuropathology, University Medical Center Hamburg-Eppendorf , 20246 Hamburg,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Hoffmeister-Ullerich","sequence":"additional","affiliation":[{"name":"Bioanalytics, Scientific Service Groups, Center for Molecular Neurobiology , 20251 Hamburg,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M C","family":"Binder","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf , 20246 Hamburg,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H","family":"Eiermann","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, University Medical Center Hamburg-Eppendorf , 20246 Hamburg,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Martin","sequence":"additional","affiliation":[{"name":"Institute for Neuroimmunology and Clinical Multiple Sclerosis Research, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf , 20251 Hamburg,","place":["Germany"]},{"name":"Department of Neuroimmunology and Multiple Sclerosis Research, Neurology Clinic, University Hospital, University of Z\u00fcrich , 8091 Z\u00fcrich,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mireia","family":"Sospedra","sequence":"additional","affiliation":[{"name":"Institute for Neuroimmunology and Clinical Multiple Sclerosis Research, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf , 20251 Hamburg,","place":["Germany"]},{"name":"Department of Neuroimmunology and Multiple Sclerosis Research, Neurology Clinic, University Hospital, University of Z\u00fcrich , 8091 Z\u00fcrich,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,10,1]]},"reference":[{"key":"2025032409264236900_r1","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1038\/nature01441","article-title":"CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes","volume":"421","author":"Janssen","year":"2003","journal-title":"Nature"},{"key":"2025032409264236900_r2","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1126\/science.1084511","article-title":"Immunology. 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