{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T13:27:30Z","timestamp":1786973250244,"version":"build-2736575974"},"reference-count":20,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":216,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012621","name":"University College London Hospitals Biomedical Research Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012621","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100022431","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/T001313\/1"],"award-info":[{"award-number":["MR\/T001313\/1"]}],"id":[{"id":"10.13039\/501100022431","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015873","name":"National Brain Appeal","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015873","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>NMDA receptor antibody-associated (NMDAR-Ab) encephalitis primarily affects young women and children and often requires prolonged intensive care admission. Currently available first- and second-line therapies are effective, but patients can be refractory and residual deficits are not uncommon. Although B-cell lineages and specific NMDAR (NR1 subunit) antibodies have been examined in detail, the subtypes and roles of antigen-specific T cells in providing T-cell help to drive the IgG antibody response, cytotoxic effects or other roles have not been reported. Peripheral blood mononuclear cells from eight patients and eight healthy volunteers underwent three rounds of stimulation with pooled 15-mer peptides spanning the length of the NR1 sequence. At each round of stimulation, functional CD4+ and CD8+ T-cell responses to NR1-derived peptide pools were assessed using flow cytometry. CD4+ and CD8+ T responses to NR1-derived peptide pools were identified in both patients and healthy volunteers. Patient CD4+ T-cell responses were more frequent compared to healthy volunteers after the first round of stimulation, with fewer responses after the third round. Healthy volunteer CD4+ T cells showed the opposite trend (P = 0.004, \u03c7\u00b2 test for trend). Patient CD8+ T-cell responses were also stronger than healthy volunteers after just one round of stimulation, but not thereafter. Surprisingly, both patient and healthy volunteer CD8+ T cells responded more strongly to NR1-peptide pools than CD4+ T cells. Epitope mapping after round 3 identified two NR1 peptide epitopes as targets for CD4+ T cells and eight peptide epitopes as targets for CD8+ T cells. These epitopes were distributed throughout the NR1 sequence and were distant from the well-established antibody epitope. Although the kinetics of the responses to NR1 peptides in patients may be compatible with in vivo priming of autoreactive T cells or their reduced regulation, overall, the difference between patient and healthy volunteer responses was modest. Further investigation is needed to better characterize these responses and determine their implications for disease pathogenesis, prognosis and therapy. The existence of natural responses to NR1 as a potential autoantigen, particularly in the CD8+ T-cell lineage, should also be explored.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag298","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T11:43:20Z","timestamp":1785843800000},"source":"Crossref","is-referenced-by-count":0,"title":["Incomplete T-cell tolerance and epitope-specific responses to the NR1 subunit in NMDA receptor antibody-associated encephalitis"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9932-0228","authenticated-orcid":false,"given":"Rachel L","family":"Brown","sequence":"first","affiliation":[{"name":"UCL Institute of Immunity and Transplantation, University College London , London NW3 2PP ,","place":["UK"]},{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["UK"]},{"name":"National Hospital for Neurology and Neurosurgery, University College London Hospitals Foundation NHS Trust , London WC1N 3BG ,","place":["UK"]},{"name":"National Institute for Health and Care Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre , London NW1 2PG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3391-0396","authenticated-orcid":false,"given":"Adriana","family":"Albuquerque","sequence":"additional","affiliation":[{"name":"UCL Institute of Immunity and Transplantation, University College London , London NW3 2PP ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharyn","family":"Thomas","sequence":"additional","affiliation":[{"name":"UCL Institute of Immunity and Transplantation, University College London , London NW3 2PP ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Holler","sequence":"additional","affiliation":[{"name":"UCL Institute of Immunity and Transplantation, University College London , London NW3 2PP ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Angus-Leppan","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, Royal Free Hospitals NHS Foundation Trust , London NW3 2QG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Sette","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease, Division of Vaccine Discovery, La Jolla Institute for Immunology , San Diego, CA 92037 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Lindestam Arlehamn","sequence":"additional","affiliation":[{"name":"Center for Infectious Disease, Division of Vaccine Discovery, La Jolla Institute for Immunology , San Diego, CA 92037 ,","place":["USA"]},{"name":"Centre for Vaccine Research, Department of Infectious Disease Immunology, Statens Serum Institut , 5 Artillerivej, DK-2300 Copenhagen S, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Hart","sequence":"additional","affiliation":[{"name":"Department of Neuroinflammation, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9612-9401","authenticated-orcid":false,"given":"Michael S","family":"Zandi","sequence":"additional","affiliation":[{"name":"National Hospital for Neurology and Neurosurgery, University College London Hospitals Foundation NHS Trust , London WC1N 3BG ,","place":["UK"]},{"name":"Department of Neuroinflammation, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2395-8695","authenticated-orcid":false,"given":"Angela","family":"Vincent","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans J","family":"Stauss","sequence":"additional","affiliation":[{"name":"UCL Institute of Immunity and Transplantation, University College London , London NW3 2PP ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3174-6027","authenticated-orcid":false,"given":"Michael P","family":"Lunn","sequence":"additional","affiliation":[{"name":"Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London , London WC1N 3BG ,","place":["UK"]},{"name":"National Hospital for Neurology and Neurosurgery, University College London Hospitals Foundation NHS Trust , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma C","family":"Morris","sequence":"additional","affiliation":[{"name":"UCL Institute of Immunity and Transplantation, University College London , London NW3 2PP ,","place":["UK"]},{"name":"National Institute for Health and Care Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre , London NW1 2PG ,","place":["UK"]},{"name":"Department of Clinical Neurosciences, Royal Free Hospitals NHS Foundation Trust , London NW3 2QG ,","place":["UK"]},{"name":"Department of Clinical Haematology, University College London Hospitals Foundation NHS Trust , London NW1 2PG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"issue":"12","key":"2026081708564266300_fcag298-B1","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/S1474-4422(08)70224-2","article-title":"Anti-NMDA-receptor encephalitis: Case series and analysis of the effects of antibodies","volume":"7","author":"Dalmau","year":"2008","journal-title":"Lancet Neurol"},{"issue":"3","key":"2026081708564266300_fcag298-B2","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.3390\/ijms24032540","article-title":"NMDA receptor and its emerging role in cancer","volume":"24","author":"Gallo","year":"2023","journal-title":"Int J Mol Sci"},{"issue":"6","key":"2026081708564266300_fcag298-B3","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1093\/brain\/awae410","article-title":"Neuro-immunobiology and treatment assessment in a mouse model of anti-NMDAR encephalitis","volume":"148","author":"Maudes","year":"2025","journal-title":"Brain"},{"issue":"11","key":"2026081708564266300_fcag298-B4","doi-asserted-by":"crossref","first-page":"2458","DOI":"10.3390\/biomedicines12112458","article-title":"Specific and polyfunctional T cell response against N-methyl-d-aspartate receptor in an autoantibody-mediated encephalitis model","volume":"12","author":"Lesec","year":"2024","journal-title":"Biomedicines"},{"issue":"2","key":"2026081708564266300_fcag298-B5","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1097\/CCM.0b013e3181cb0968","article-title":"Anti-N-methyl-D-aspartate receptor antibodies: A potentially treatable cause of encephalitis in the intensive care unit","volume":"38","author":"Davies","year":"2010","journal-title":"Crit Care Med"},{"issue":"4","key":"2026081708564266300_fcag298-B6","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1164\/rccm.201603-0507OC","article-title":"Anti-N-methyl-D-aspartate receptor encephalitis in adult patients requiring intensive care","volume":"195","author":"De Montmollin","year":"2017","journal-title":"Am J Respir Crit Care Med"},{"issue":"2","key":"2026081708564266300_fcag298-B7","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S1474-4422(12)70310-1","article-title":"Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: An observational cohort study","volume":"12","author":"Titulaer","year":"2013","journal-title":"Lancet Neurol"},{"issue":"9","key":"2026081708564266300_fcag298-B8","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.biopsych.2015.02.024","article-title":"Structural hippocampal damage following anti-N-methyl-D-aspartate receptor encephalitis","volume":"79","author":"Finke","year":"2016","journal-title":"Biol Psychiatry"},{"issue":"32","key":"2026081708564266300_fcag298-B9","doi-asserted-by":"crossref","first-page":"11082\u2013","DOI":"10.1523\/JNEUROSCI.0064-12.2012","article-title":"Anti-NMDA receptor encephalitis antibody binding is dependent on amino acid identity of a small region within the GluN1 amino terminal domain","volume":"32","author":"Gleichman","year":"2012","journal-title":"J Neurosci"},{"issue":"8","key":"2026081708564266300_fcag298-B10","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1093\/brain\/awae163","article-title":"NMDA receptor autoantibodies primarily impair the extrasynaptic compartment","volume":"147","author":"Jamet","year":"2024","journal-title":"Brain"},{"issue":"6","key":"2026081708564266300_fcag298-B11","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1007\/s00415-020-10371-y","article-title":"Decreased inflammatory cytokine production of antigen-specific CD4+ T cells in NMDA receptor encephalitis","volume":"268","author":"Dao","year":"2021","journal-title":"J Neurol"},{"key":"2026081708564266300_fcag298-B12","doi-asserted-by":"crossref","DOI":"10.1016\/j.coi.2025.102705","article-title":"The role of linked recognition and B cell precursor frequency in alloimmunization to transfused RBCs","volume":"98","author":"Frost","year":"2026","journal-title":"Curr Opin Immunol"},{"issue":"4","key":"2026081708564266300_fcag298-B13","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1038\/nri1334","article-title":"T-cell\u2013B-cell cooperation","volume":"4","author":"Mitchison","year":"2004","journal-title":"Nat Rev Immunol"},{"issue":"11","key":"2026081708564266300_fcag298-B14","doi-asserted-by":"crossref","first-page":"e934","DOI":"10.1002\/cpz1.934","article-title":"The MegaPool approach to characterize adaptive CD4+ and CD8+ T cell responses","volume":"3","author":"da Silva Antunes","year":"2023","journal-title":"Curr Protoc"},{"issue":"19","key":"2026081708564266300_fcag298-B15","doi-asserted-by":"crossref","first-page":"9144","DOI":"10.1128\/JVI.74.19.9144-9151.2000","article-title":"Putative immunodominant human immunodeficiency virus-specific CD8+ T-cell responses cannot be predicted by major histocompatibility complex class I haplotype","volume":"74","author":"Betts","year":"2000","journal-title":"J Virol"},{"issue":"7725","key":"2026081708564266300_fcag298-B16","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/s41586-018-0540-1","article-title":"T cells in patients with narcolepsy target self-antigens of hypocretin neurons","volume":"562","author":"Latorre","year":"2018","journal-title":"Nature"},{"issue":"7997","key":"2026081708564266300_fcag298-B17","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/s41586-023-06916-6","article-title":"Autoreactive T cells target peripheral nerves in Guillain\u2013Barr\u00e9 syndrome","volume":"626","author":"S\u00faken\u00edkov\u00e1","year":"2024","journal-title":"Nature"},{"key":"2026081708564266300_fcag298-B18","doi-asserted-by":"crossref","DOI":"10.1016\/j.intimp.2024.111743","article-title":"Blood and CSF findings of cellular immunity in anti-NMDAR encephalitis","volume":"130","author":"Wang","year":"2024","journal-title":"Int Immunopharmacol"},{"issue":"7","key":"2026081708564266300_fcag298-B19","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1097\/CM9.0000000000003742","article-title":"Single-cell multi-omics reveals compartmentalized heterogeneity, clonal dynamics, and B cell interplay of CD8 + T cell subsets in anti-NMDAR encephalitis","volume":"139","author":"Li","year":"2026","journal-title":"Chin Med J"},{"issue":"10","key":"2026081708564266300_fcag298-B20","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1016\/j.immuni.2024.08.005","article-title":"Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases","volume":"57","author":"Saggau","year":"2024","journal-title":"Immunity"}],"container-title":["Brain Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/braincomms\/advance-article-pdf\/doi\/10.1093\/braincomms\/fcag298\/70499631\/fcag298.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/8\/4\/fcag298\/70499631\/fcag298.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/8\/4\/fcag298\/70499631\/fcag298.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:56:52Z","timestamp":1786971412000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/braincomms\/article\/doi\/10.1093\/braincomms\/fcag298\/8752837"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":20,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,7,1]]}},"URL":"https:\/\/doi.org\/10.1093\/braincomms\/fcag298","relation":{},"ISSN":["2632-1297"],"issn-type":[{"value":"2632-1297","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026]]},"published":{"date-parts":[[2026]]},"article-number":"fcag298"}}