{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:32:42Z","timestamp":1792071162394,"version":"4.4.0"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,12,29]],"date-time":"2019-12-29T00:00:00Z","timestamp":1577577600000},"content-version":"vor","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81471222"],"award-info":[{"award-number":["81471222"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Taishan Scholars Construction Engineering of Shandong Province","award":["ts20130914"],"award-info":[{"award-number":["ts20130914"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neuroinflammation"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>Recent studies have demonstrated that natural killer (NK) cells can modulate other immune components and are involved in the development or progression of several autoimmune diseases. However, the roles and mechanisms of NK cells in regulating experimental autoimmune myasthenia gravis (EAMG) remained to be illustrated.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>To address the function of NK cells in experimental autoimmune myasthenia gravis in vivo, EAMG rats were adoptively transferred with splenic NK cells. The serum antibodies, and splenic follicular helper T (Tfh) cells and germinal center B cells were determined by ELISA and flow cytometry. The roles of NK cells in regulating Tfh cells were further verified in vitro by co-culturing splenocytes or isolated T cells with NK cells. Moreover, the phenotype, localization, and function differences between different NK cell subtypes were determined by flow cytometry, immunofluorescence, and ex vivo co-culturation.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>In this study, we found that adoptive transfer of NK cells ameliorated EAMG symptoms by suppressing Tfh cells and germinal center B cells. Ex vivo studies indicated NK cells inhibited CD4<jats:sup>+<\/jats:sup> T cells and Tfh cells by inducing the apoptosis of T cells. More importantly, NK cells could be divided into CXCR5<jats:sup>-<\/jats:sup> and CXCR5<jats:sup>+<\/jats:sup> NK subtypes according to the expression of CXCR5 molecular. Compared with CXCR5<jats:sup>-<\/jats:sup> NK cells, which were mainly localized outside B cell zone, CXCR5<jats:sup>+<\/jats:sup> NK were concentrated in the B cell zone and exhibited higher expression levels of IL-17 and ICOS, and lower expression level of CD27. Ex vivo studies indicated it was CXCR5<jats:sup>-<\/jats:sup> NK cells not CXCR5<jats:sup>+<\/jats:sup> NK cells that suppressed CD4<jats:sup>+<\/jats:sup> T cells and Tfh cells. Further analysis revealed that, compared with CXCR5<jats:sup>-<\/jats:sup> NK cells, CXCR5<jats:sup>+<\/jats:sup> NK cells enhanced the ICOS expression of Tfh cells.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>These findings highlight the different roles of CXCR5<jats:sup>-<\/jats:sup> NK cells and CXCR5<jats:sup>+<\/jats:sup> NK cells. It was CXCR5<jats:sup>-<\/jats:sup> NK cells but not CXCR5<jats:sup>+<\/jats:sup> NK cells that suppressed Tfh cells and inhibited the autoimmune response in EAMG models.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s12974-019-1687-x","type":"journal-article","created":{"date-parts":[[2019,12,29]],"date-time":"2019-12-29T05:02:19Z","timestamp":1577595739000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["CXCR5-negative natural killer cells ameliorate experimental autoimmune myasthenia gravis by suppressing follicular helper T cells"],"prefix":"10.1186","volume":"16","author":[{"given":"Chun-Lin","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru-Tao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Li","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Chun","family":"Dou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7481-7641","authenticated-orcid":false,"given":"Rui-Sheng","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,29]]},"reference":[{"key":"1687_CR1","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.coi.2017.07.006","volume":"49","author":"F Romi","year":"2017","unstructured":"Romi F, Hong Y, Gilhus NE. Pathophysiology and immunological profile of myasthenia gravis and its subgroups. Curr Opin Immunol. 2017;49:9\u201313.","journal-title":"Curr Opin Immunol"},{"key":"1687_CR2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1701027","volume":"376","author":"NE Gilhus","year":"2017","unstructured":"Gilhus NE. Myasthenia gravis. N Engl J Med. 2017;376:e25.","journal-title":"N Engl J Med"},{"key":"1687_CR3","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.coi.2016.08.003","volume":"43","author":"H Ueno","year":"2016","unstructured":"Ueno H. T follicular helper cells in human autoimmunity. Curr Opin Immunol. 2016;43:24\u201331.","journal-title":"Curr Opin Immunol"},{"key":"1687_CR4","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.jneuroim.2012.12.001","volume":"256","author":"C Luo","year":"2013","unstructured":"Luo C, Li Y, Liu W, Feng H, Wang H, Huang X, et al. Expansion of circulating counterparts of follicular helper T cells in patients with myasthenia gravis. J Neuroimmunol. 2013;256:55\u201361.","journal-title":"J Neuroimmunol"},{"key":"1687_CR5","doi-asserted-by":"publisher","first-page":"2610","DOI":"10.4049\/jimmunol.1500725","volume":"197","author":"CJ Zhang","year":"2016","unstructured":"Zhang CJ, Gong Y, Zhu W, Qi Y, Yang CS, Fu Y, et al. Augmentation of circulating follicular helper T cells and their impact on autoreactive B cells in Myasthenia gravis. J Immunol. 2016;197:2610\u20137.","journal-title":"J Immunol"},{"key":"1687_CR6","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1007\/s12035-014-8985-1","volume":"53","author":"X Zhang","year":"2016","unstructured":"Zhang X, Liu S, Chang T, Xu J, Zhang C, Tian F, et al. Intrathymic Tfh\/B cells interaction leads to ectopic GCs formation and anti-AChR antibody production: Central Role in Triggering MG Occurrence. Mol Neurobiol. 2016;53:120\u201331.","journal-title":"Mol Neurobiol"},{"key":"1687_CR7","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.mcn.2013.12.006","volume":"58","author":"N Xin","year":"2014","unstructured":"Xin N, Fu L, Shao Z, Guo M, Zhang X, Zhang Y, et al. RNA interference targeting Bcl-6 ameliorates experimental autoimmune myasthenia gravis in mice. Mol Cell Neurosci. 2014;58:85\u201394.","journal-title":"Mol Cell Neurosci"},{"key":"1687_CR8","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1016\/j.immuni.2017.10.008","volume":"47","author":"AG Freud","year":"2017","unstructured":"Freud AG, Mundy-Bosse BL, Yu J, Caligiuri MA. The broad spectrum of human natural killer cell diversity. Immunity. 2017;47:820\u201333.","journal-title":"Immunity"},{"key":"1687_CR9","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/j.it.2013.03.002","volume":"34","author":"SQ Crome","year":"2013","unstructured":"Crome SQ, Lang PA, Lang KS, Ohashi PS. Natural killer cells regulate diverse T cell responses. Trends Immunol. 2013;34:342\u20139.","journal-title":"Trends Immunol"},{"key":"1687_CR10","doi-asserted-by":"publisher","first-page":"352","DOI":"10.2119\/molmed.2009.00035","volume":"15","author":"A Lunemann","year":"2009","unstructured":"Lunemann A, Lunemann JD, Munz C. Regulatory NK-cell functions in inflammation and autoimmunity. Mol Med. 2009;15:352\u20138.","journal-title":"Mol Med"},{"key":"1687_CR11","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.immuni.2014.09.013","volume":"41","author":"IS Schuster","year":"2014","unstructured":"Schuster IS, Wikstrom ME, Brizard G, Coudert JD, Estcourt MJ, Manzur M, et al. TRAIL+ NK cells control CD4+ T cell responses during chronic viral infection to limit autoimmunity. Immunity. 2014;41:646\u201356.","journal-title":"Immunity"},{"key":"1687_CR12","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1073\/pnas.1118834109","volume":"109","author":"PA Lang","year":"2012","unstructured":"Lang PA, Lang KS, Xu HC, Grusdat M, Parish IA, Recher M, et al. Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. Proc Natl Acad Sci U S A. 2012;109:1210\u20135.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1687_CR13","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1172\/JCI41264","volume":"120","author":"SN Waggoner","year":"2010","unstructured":"Waggoner SN, Taniguchi RT, Mathew PA, Kumar V, Welsh RM. Absence of mouse 2B4 promotes NK cell-mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis. J Clin Invest. 2010;120:1925\u201338.","journal-title":"J Clin Invest"},{"key":"1687_CR14","doi-asserted-by":"publisher","first-page":"E6202","DOI":"10.1073\/pnas.1705491114","volume":"114","author":"W Jiang","year":"2017","unstructured":"Jiang W, Li D, Han R, Zhang C, Jin WN, Wood K, et al. Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes\/macrophages. Proc Natl Acad Sci U S A. 2017;114:E6202\u201311.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1687_CR15","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1189\/jlb.4HI1214-594R","volume":"98","author":"KD Cook","year":"2015","unstructured":"Cook KD, Kline HC, Whitmire JK. NK cells inhibit humoral immunity by reducing the abundance of CD4+ T follicular helper cells during a chronic virus infection. J Leukoc Biol. 2015;98:153\u201362.","journal-title":"J Leukoc Biol"},{"key":"1687_CR16","doi-asserted-by":"publisher","first-page":"3367","DOI":"10.1016\/j.celrep.2018.08.075","volume":"24","author":"CE Rydyznski","year":"2018","unstructured":"Rydyznski CE, Cranert SA, Zhou JQ, Xu H, Kleinstein SH, Singh H, et al. Affinity maturation is impaired by natural killer cell suppression of germinal centers. Cell Reports. 2018;24:3367\u201373 e3364.","journal-title":"Cell Reports"},{"key":"1687_CR17","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.molimm.2018.01.005","volume":"94","author":"P Zhang","year":"2018","unstructured":"Zhang P, Yang CL, Liu RT, Li H, Zhang M, Zhang N, et al. Toll-like receptor 9 antagonist suppresses humoral immunity in experimental autoimmune myasthenia gravis. Mol Immunol. 2018;94:200\u20138.","journal-title":"Mol Immunol"},{"key":"1687_CR18","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.jneuroim.2018.11.008","volume":"326","author":"SX Wang","year":"2019","unstructured":"Wang SX, Yang CL, Zhang M, Zhang P, Liu RT, Zhang N, et al. Sulfatides ameliorate experimental autoimmune neuritis by suppressing Th1\/Th17 cells. J Neuroimmunol. 2019;326:55\u201361.","journal-title":"J Neuroimmunol"},{"key":"1687_CR19","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/j.mcn.2015.08.010","volume":"68","author":"H Li","year":"2015","unstructured":"Li H, Wang CC, Zhang M, Li XL, Zhang P, Yue LT, et al. Statin-modified dendritic cells regulate humoral immunity in experimental autoimmune myasthenia gravis. Mol Cell Neurosci. 2015;68:284\u201392.","journal-title":"Mol Cell Neurosci"},{"key":"1687_CR20","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1038\/ni.1715","volume":"10","author":"RL Reinhardt","year":"2009","unstructured":"Reinhardt RL, Liang HE, Locksley RM. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat Immunol. 2009;10:385\u201393.","journal-title":"Nat Immunol"},{"key":"1687_CR21","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1016\/j.jaci.2015.04.001","volume":"136","author":"C Yao","year":"2015","unstructured":"Yao C, Zurawski SM, Jarrett ES, Chicoine B, Crabtree J, Peterson EJ, et al. Skin dendritic cells induce follicular helper T cells and protective humoral immune responses. J Allergy Clin Immunol. 2015;136:1387\u201397 e1381-1387.","journal-title":"J Allergy Clin Immunol"},{"key":"1687_CR22","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1038\/ni.3793","volume":"18","author":"SJ Kim","year":"2017","unstructured":"Kim SJ, Schatzle S, Ahmed SS, Haap W, Jang SH, Gregersen PK, et al. Increased cathepsin S in Prdm1(-\/-) dendritic cells alters the TFH cell repertoire and contributes to lupus. Nat Immunol. 2017;18:1016\u201324.","journal-title":"Nat Immunol"},{"key":"1687_CR23","doi-asserted-by":"publisher","first-page":"1905","DOI":"10.1016\/j.jid.2017.04.016","volume":"137","author":"C Levin","year":"2017","unstructured":"Levin C, Bonduelle O, Nuttens C, Primard C, Verrier B, Boissonnas A, et al. Critical role for skin-derived migratory DCs and Langerhans cells in TFH and GC responses after intradermal immunization. J Invest Dermatol. 2017;137:1905\u201313.","journal-title":"J Invest Dermatol"},{"key":"1687_CR24","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1615\/CritRevImmunol.2018025248","volume":"38","author":"J Freund-Brown","year":"2018","unstructured":"Freund-Brown J, Chirino L, Kambayashi T. Strategies to enhance NK cell function for the treatment of tumors and infections. Crit Rev Immunol. 2018;38:105\u201330.","journal-title":"Crit Rev Immunol"},{"key":"1687_CR25","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1084\/jem.184.2.349","volume":"184","author":"GX Zhang","year":"1996","unstructured":"Zhang GX, Xiao BG, Bakhiet M, van der Meide P, Wigzell H, Link H, et al. Both CD4+ and CD8+ T cells are essential to induce experimental autoimmune myasthenia gravis. J Exp Med. 1996;184:349\u201356.","journal-title":"J Exp Med"},{"key":"1687_CR26","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/79792","volume":"1","author":"FD Shi","year":"2000","unstructured":"Shi FD, Wang HB, Li H, Hong S, Taniguchi M, Link H, et al. Natural killer cells determine the outcome of B cell-mediated autoimmunity. Nat Immunol. 2000;1:245\u201351.","journal-title":"Nat Immunol"},{"key":"1687_CR27","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.3389\/fimmu.2018.02277","volume":"9","author":"DJ Wikenheiser","year":"2018","unstructured":"Wikenheiser DJ, Brown SL, Lee J, Stumhofer JS. NK1.1 Expression defines a population of CD4(+) effector T cells displaying Th1 and Tfh cell properties that support early antibody production during Plasmodium yoelii infection. Front Immunol. 2018;9:2277.","journal-title":"Front Immunol"},{"key":"1687_CR28","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1182\/blood-2006-10-052720","volume":"110","author":"C Cerboni","year":"2007","unstructured":"Cerboni C, Zingoni A, Cippitelli M, Piccoli M, Frati L, Santoni A. Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM\/ATR-dependent mechanism and become susceptible to autologous NK- cell lysis. Blood. 2007;110:606\u201315.","journal-title":"Blood"},{"key":"1687_CR29","doi-asserted-by":"publisher","first-page":"27615","DOI":"10.1038\/srep27615","volume":"6","author":"JH Kim","year":"2016","unstructured":"Kim JH, Choi GE, Lee BJ, Kwon SW, Lee SH, Kim HS, et al. Natural killer cells regulate eosinophilic inflammation in chronic rhinosinusitis. Sci Rep. 2016;6:27615.","journal-title":"Sci Rep"},{"key":"1687_CR30","doi-asserted-by":"publisher","first-page":"1668","DOI":"10.4049\/jimmunol.1102002","volume":"188","author":"FB Thoren","year":"2012","unstructured":"Thoren FB, Riise RE, Ousback J, Della Chiesa M, Alsterholm M, Marcenaro E, et al. Human NK Cells induce neutrophil apoptosis via an NKp46- and Fas-dependent mechanism. J Immunol. 2012;188:1668\u201374.","journal-title":"J Immunol"},{"key":"1687_CR31","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/0165-2478(90)90036-P","volume":"24","author":"T Commes","year":"1990","unstructured":"Commes T, Clofent G, Jourdan M, Bataille R, Klein B. Human natural killer cells suppress the proliferation of B cells. Immunol Lett. 1990;24:57\u201361.","journal-title":"Immunol Lett"},{"key":"1687_CR32","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.jaut.2012.05.006","volume":"39","author":"Z Tian","year":"2012","unstructured":"Tian Z, Gershwin ME, Zhang C. Regulatory NK cells in autoimmune disease. J Autoimmun. 2012;39:206\u201315.","journal-title":"J Autoimmun"},{"key":"1687_CR33","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1038\/nm.4421","volume":"23","author":"N Huot","year":"2017","unstructured":"Huot N, Jacquelin B, Garcia-Tellez T, Rascle P, Ploquin MJ, Madec Y, et al. Natural killer cells migrate into and control simian immunodeficiency virus replication in lymph node follicles in African green monkeys. Nat Med. 2017;23:1277\u201386.","journal-title":"Nat Med"},{"key":"1687_CR34","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1038\/35051107","volume":"409","author":"AJ McAdam","year":"2001","unstructured":"McAdam AJ, Greenwald RJ, Levin MA, Chernova T, Malenkovich N, Ling V, et al. ICOS is critical for CD40-mediated antibody class switching. Nature. 2001;409:102\u20135.","journal-title":"Nature"}],"container-title":["Journal of Neuroinflammation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-019-1687-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12974-019-1687-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12974-019-1687-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,28]],"date-time":"2020-12-28T00:07:03Z","timestamp":1609114023000},"score":1,"resource":{"primary":{"URL":"https:\/\/jneuroinflammation.biomedcentral.com\/articles\/10.1186\/s12974-019-1687-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12]]},"references-count":34,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["1687"],"URL":"https:\/\/doi.org\/10.1186\/s12974-019-1687-x","relation":{},"ISSN":["1742-2094"],"issn-type":[{"value":"1742-2094","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12]]},"assertion":[{"value":"8 September 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 December 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 December 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All the animal experimental protocols were approved by the Ethics Committee of Shandong Provincial Qianfoshan Hospital.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"282"}}