{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T01:41:56Z","timestamp":1789609316884,"version":"build-2803163510"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2018,3,24]],"date-time":"2018-03-24T00:00:00Z","timestamp":1521849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,7,10]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Studies of cerebrospinal fluid (CSF) \u03b3\u03b4 T cells in children are limited, due\u00a0especially to the lack of control data. In adults, gamma\/delta T cells (TCR-\u03b3\u03b4) residing in the intrathecal space are sometimes involved in neuroinflammation. To evaluate the possible role of \u03b3\u03b4 T cells in paediatric neuroinflammation, we immunophenotyped cerebrospinal fluid (CSF) and blood lymphocytes using flow cytometry in a case\u2013control study of 100 children with non-inflammatory neurological disorders (NIND), 312 with opsoclonus\u2013myoclonus (OMS) and 23 with other inflammatory neurological disorders (OIND). In NIND, the negative correlation between CSF \u03b3\u03b4 T cell frequency and patient age was striking: median frequency of 27% in infants and 3\u00b73% in teens. Interindividual variations were largest in the youngest. There was no gender effect. In all OMS, after correcting for age, only a small effect of OMS severity remained. Measurement of markers for \u03b3\u03b4 T cell activation [human leucocyte antigen D-related (HLA-DR)], maturation (CD45RA, CD45RO) or intracellular cytokine staining [interleukin (IL)-4, interferon (IFN)-\u03b3] failed to discriminate OMS and NIND groups. Of seven OMS immunotherapies\/combinations, none altered the frequency of total CSF \u03b3\u03b4 T cells or subsets significantly. In OIND, the CSF \u03b3\u03b4 T cell frequency was &amp;lt;\u00a010% for single samples of other paraneoplastic disorders [anti-neuronal nuclear antibody (ANNA)-1, PCA-1, teratoma-associated syndrome], cerebellar ataxia (post-infectious, ataxia-telangiectasia), acute disseminated encephalomyelitis, neuroborreliosis and encephalitis. This study provides new insights into CSF \u03b3\u03b4 T cells in the paediatric population. Although their role in CSF remains elusive, the negative age correlation, resistance to immunotherapy and our age cut-off references for NIND are important findings for the design of future paediatric studies.<\/jats:p>","DOI":"10.1111\/cei.13122","type":"journal-article","created":{"date-parts":[[2018,2,27]],"date-time":"2018-02-27T16:23:10Z","timestamp":1519748590000},"page":"103-112","source":"Crossref","is-referenced-by-count":6,"title":["Cerebrospinal fluid \u03b3\u03b4 T cell frequency is age-related: a case\u2013control study of 435 children with inflammatory and non-inflammatory neurological disorders"],"prefix":"10.1093","volume":"193","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6091-8989","authenticated-orcid":false,"given":"M R","family":"Pranzatelli","sequence":"first","affiliation":[{"name":"National Pediatric Myoclonus Center, Orlando, FL, USA"},{"name":"National Pediatric Neuroinflammation Organization, Inc., Orlando, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T J","family":"Allison","sequence":"additional","affiliation":[{"name":"National Pediatric Myoclonus Center, Orlando, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N R","family":"McGee","sequence":"additional","affiliation":[{"name":"National Pediatric Myoclonus Center, Orlando, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E D","family":"Tate","sequence":"additional","affiliation":[{"name":"National Pediatric Myoclonus Center, Orlando, FL, USA"},{"name":"National Pediatric Neuroinflammation Organization, Inc., Orlando, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,3,24]]},"reference":[{"key":"2021120808395865100_cei13122-bib-0001","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.4049\/jimmunol.172.3.1637","article-title":"Ontogeny of gamma delta T cells in humans","volume":"172","author":"De Rosa","year":"2004","journal-title":"J Immunol"},{"key":"2021120808395865100_cei13122-bib-0002","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1146\/annurev.immunol.18.1.975","article-title":"\u03b3\u03b4 Cells: a right time and right place for a conserved third way of protection","volume":"18","author":"Hayday","year":"2000","journal-title":"Annu Rev Immunol"},{"key":"2021120808395865100_cei13122-bib-0003","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1146\/annurev.iy.11.040193.003225","article-title":"Gamma\/delta cells","volume":"11","author":"Haas","year":"1993","journal-title":"Annu Rev Immunol"},{"key":"2021120808395865100_cei13122-bib-0004","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S0065-2776(08)60400-9","article-title":"Immunoregulatory functions of \u03b3\u03b4 T-cells","volume":"71","author":"Born","year":"1999","journal-title":"Adv Immunol"},{"key":"2021120808395865100_cei13122-bib-0005","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1111\/j.1600-065X.2006.00470.x","article-title":"Antigen recognition by gammadelta T cells","volume":"215","author":"Chien","year":"2007","journal-title":"Immunol Rev"},{"key":"2021120808395865100_cei13122-bib-0006","doi-asserted-by":"crossref","first-page":"210","DOI":"10.3389\/fimmu.2016.00210","article-title":"Chronic inflammation and \u03b3\u03b4 T cells","volume":"7","author":"Fay","year":"2016","journal-title":"Front Immunol"},{"key":"2021120808395865100_cei13122-bib-0007","doi-asserted-by":"crossref","first-page":"5622","DOI":"10.4049\/jimmunol.0901772","article-title":"Human gamma delta T cells: a lymphoid lineage cell capable of professional phagocytosis","volume":"183","author":"Wu","year":"2009","journal-title":"J Immunol"},{"key":"2021120808395865100_cei13122-bib-0008","doi-asserted-by":"crossref","first-page":"4678","DOI":"10.4049\/jimmunol.174.8.4678","article-title":"Gamma delta T cells regulate the extent and duration of inflammation in the central nervous system by a Fas ligand-dependent mechanism","volume":"174","author":"Ponomarev","year":"2005","journal-title":"J Immunol"},{"key":"2021120808395865100_cei13122-bib-0009","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.immuni.2010.08.013","article-title":"Gamma delta T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism","volume":"33","author":"Peterman","year":"2010","journal-title":"Immunity"},{"key":"2021120808395865100_cei13122-bib-0010","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/j.1365-3083.1990.tb02797.x","article-title":"CD4+, CD8+, and CD4\u2013 CD8\u2013 T cells in CSF and blood of patients with multiple sclerosis and tension headache","volume":"31","author":"Mix","year":"1990","journal-title":"Scand J Immunol"},{"key":"2021120808395865100_cei13122-bib-0011","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1177\/135245859600200203","article-title":"Oligoclonal expansion of gamma delta T-cells in cerebrospinal fluid of multiple sclerosis patients","volume":"2","author":"Bieganowski","year":"1996","journal-title":"Mult Scler"},{"key":"2021120808395865100_cei13122-bib-0012","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1001\/2013.jamaneurol.409","article-title":"Enriched CD161high CCR6+\u03b3\u03b4 T cells in the cerebrospinal fluid of patients with multiple sclerosis","volume":"70","author":"Schirmer","year":"2013","journal-title":"JAMA Neurol"},{"key":"2021120808395865100_cei13122-bib-0013","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/eji.1830250208","article-title":"T-cell receptor \u03b3\u03b4 repertoire is skewed in cerebrospinal fluid of multiple sclerosis patients: molecular and functional analyses of antigen-reactive \u03b3\u03b4 clones","volume":"25","author":"Nick","year":"1995","journal-title":"Eur J Immunol"},{"key":"2021120808395865100_cei13122-bib-0014","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/s12974-015-0352-2","article-title":"Evidence for involvement of gamma delta T cells in the immune response to Rasmussen encephalitis","volume":"12","author":"Owens","year":"2015","journal-title":"J Neuroinflammation"},{"key":"2021120808395865100_cei13122-bib-0015","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.cellimm.2014.04.013","article-title":"T cell subsets play opposing roles in regulating experimental autoimmune encephalitis","volume":"290","author":"Blink","year":"2014","journal-title":"Cell Immunol"},{"key":"2021120808395865100_cei13122-bib-0016","doi-asserted-by":"crossref","first-page":"941","DOI":"10.4049\/jimmunol.157.2.941","article-title":"A pathogenic role for gamma delta cells in relapsing\u2013remitting experimental allergic encephalomyelitis in the SJL mouse","volume":"157","author":"Rajan","year":"1996","journal-title":"J Immunol"},{"key":"2021120808395865100_cei13122-bib-0017","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1006\/jaut.1997.0180","article-title":"Adoptively transferred EAE in gamma delta T cell-knockout mice","volume":"11","author":"Clark","year":"1998","journal-title":"J Autoimmun"},{"key":"2021120808395865100_cei13122-bib-0018","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.it.2016.07.006","article-title":"Memory \u03b3\u03b4 T cells \u2013 newly appreciated protagonists in infection and immunity","volume":"37","author":"Lalor","year":"2016","journal-title":"Trends Immunol"},{"key":"2021120808395865100_cei13122-bib-0019","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/00002826-199619010-00001","article-title":"The immunopharmacology of the opsoclonus\u2013myoclonus syndrome","volume":"19","author":"Pranzatelli","year":"1996","journal-title":"Clin Neuropharmacol"},{"key":"2021120808395865100_cei13122-bib-0020","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1136\/jnnp.25.3.271","article-title":"Myoclonic encephalopathy of infants","volume":"25","author":"Kinsbourne","year":"1962","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"2021120808395865100_cei13122-bib-0021","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1056\/NEJM196808292790907","article-title":"Opsoclonus and occult neuroblastoma","volume":"279","author":"Solomon","year":"1968","journal-title":"N Engl J Med"},{"key":"2021120808395865100_cei13122-bib-0022","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.braindev.2015.11.007","article-title":"Trends and tenets in relapsing and progressive pediatric opsoclonus-myoclonus","volume":"38","author":"Pranzatelli","year":"2016","journal-title":"Brain Dev"},{"key":"2021120808395865100_cei13122-bib-0023","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1038\/mt.2013.38","article-title":"Mechanisms of the antitumor activity of human V\u03b39V\u03b42 T cells in combination with zoledronic acid in a preclinical model of neuroblastoma","volume":"21","author":"Di Carlo","year":"2013","journal-title":"Mol Ther"},{"key":"2021120808395865100_cei13122-bib-0024","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1097\/00002371-200009000-00004","article-title":"Human gammadelta T lymphocytes exert natural and IL-2-induced cytotoxicity to neuroblastoma cells","volume":"23","author":"Schilbach","year":"2000","journal-title":"J Immunother"},{"key":"2021120808395865100_cei13122-bib-0025","doi-asserted-by":"crossref","first-page":"e27572","DOI":"10.4161\/onci.27572","article-title":"\u03b3\u03b4 T cells for cancer immunotherapy: a systematic review of clinical trials","volume":"3","author":"Fisher","year":"2014","journal-title":"Oncoimmunology"},{"key":"2021120808395865100_cei13122-bib-0026","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1212\/WNL.62.9.1526","article-title":"B- and T-cell markers in opsoclonus\u2013myoclonus syndrome: immunophenotyping of CSF lymphocytes","volume":"62","author":"Pranzatelli","year":"2004","journal-title":"Neurology"},{"key":"2021120808395865100_cei13122-bib-0027","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1002\/mds.20125","article-title":"CSF B-cell expansion in opsoclonus\u2013myoclonus syndrome: a biomarker of disease activity","volume":"19","author":"Pranzatelli","year":"2004","journal-title":"Mov Disord"},{"key":"2021120808395865100_cei13122-bib-0028","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1097\/00043426-200411000-00006","article-title":"Immunophenotype of blood lymphocytes in neuroblastoma-associated opsoclonus\u2013myoclonus","volume":"26","author":"Pranzatelli","year":"2004","journal-title":"J Pediatr Hematol Oncol"},{"key":"2021120808395865100_cei13122-bib-0029","doi-asserted-by":"crossref","first-page":"e4909","DOI":"10.1097\/MD.0000000000004909","article-title":"In vivo expansion and activation of \u03b3\u03b4 T cells as immunotherapy for refractory neuroblastoma: a phase 1 study","volume":"95","author":"Pressey","year":"2016","journal-title":"Medicine (Baltimore)"},{"key":"2021120808395865100_cei13122-bib-0030","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.4049\/jimmunol.1302884","article-title":"Comprehensive immunophenotyping of cerebrospinal fluid cells in patients with neuroimmunological diseases","volume":"192","author":"Han","year":"2014","journal-title":"J Immunol"},{"key":"2021120808395865100_cei13122-bib-0031","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/BF03402066","article-title":"Predominance of Vgamma 9\/V delta 2 T lymphocytes in the cerebrospinal fluid of children with tuberculosis meningitis: reversal after chemotherapy","volume":"5","author":"Dieli","year":"1999","journal-title":"Mol Med"},{"key":"2021120808395865100_cei13122-bib-0032","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/0165-5728(91)90004-Q","article-title":"CD5+ B cells and CD4\u20138-T cells in neuroimmunological diseases","volume":"32","author":"Correale","year":"1991","journal-title":"J Neuroimmunol"},{"key":"2021120808395865100_cei13122-bib-0033","first-page":"53","article-title":"Cerebrospinal fluid T-cell receptor gamma\/delta T lymphocyte subsets in patient with AIDS\u2013dementia complex","volume":"6","author":"Perrella","year":"1992","journal-title":"J Biol Regul Homeost Agents"},{"key":"2021120808395865100_cei13122-bib-0034","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1111\/j.1651-2227.1995.tb13546.x","article-title":"\u03b3\u03b4 T lymphocytes in mumps meningitis patients","volume":"84","author":"Bertotto","year":"1995","journal-title":"Acta Paediatr"},{"key":"2021120808395865100_cei13122-bib-0035","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/0022-510X(94)90269-0","article-title":"Gamma delta T cell distribution in cerebrospinal fluid and peripheral blood of patients with multiple sclerosis","volume":"126","author":"Droogan","year":"1994","journal-title":"J Neurol Sci"},{"key":"2021120808395865100_cei13122-bib-0036","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.5858\/132.11.1774","article-title":"Immunophenotypic attributes of benign peripheral gammadelta T cells and conditions associated with their increase","volume":"132","author":"Roden","year":"2008","journal-title":"Arch Pathol Lab Med"},{"key":"2021120808395865100_cei13122-bib-0037","first-page":"1944","article-title":"Association of methotrexate treatment with a decrease of double negative (CD4\u2013CD8\u2013) and gammadelta T cell levels in patients with juvenile rheumatoid arthritis","volume":"20","author":"Massa","year":"1993","journal-title":"J Rheumatol"},{"key":"2021120808395865100_cei13122-bib-0038","doi-asserted-by":"crossref","first-page":"5970","DOI":"10.1158\/0008-5472.CAN-16-0091","article-title":"Immune stimulatory effects of rapamycin are mediated by stimulation of antitumor \u03b3\u03b4 T cells","volume":"76","author":"Dao","year":"2016","journal-title":"Cancer Res"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcei.13122","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/193\/1\/103\/41645740\/cei13122.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/193\/1\/103\/41645740\/cei13122.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T09:40:56Z","timestamp":1693561256000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/193\/1\/103\/6411910"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,24]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,3,24]]},"published-print":{"date-parts":[[2018,7,10]]}},"URL":"https:\/\/doi.org\/10.1111\/cei.13122","relation":{},"ISSN":["0009-9104","1365-2249"],"issn-type":[{"value":"0009-9104","type":"print"},{"value":"1365-2249","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,7]]},"published":{"date-parts":[[2018,3,24]]}}}