{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T20:56:00Z","timestamp":1774644960796,"version":"3.50.1"},"reference-count":26,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"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":[[2015,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Multiple sclerosis (MS) is believed to be initiated by myelin-reactive CD4+ Th cells. IL-12\u2013polarized Th1 cells, IL-23\u2013polarized Th17 cells, and Th17 cells that acquire Th1 characteristics were each implicated in autoimmune pathogenesis. It is debated whether Th cells that can drive the development of demyelinating lesions are phenotypically diverse or arise from a single lineage. In the current study, we assessed the requirement of IL-12 or IL-23 stimulation, as well as Th plasticity, for the differentiation of T cells capable of inducing CNS axon damage. We found that stable murine Th1 and Th17 cells independently transfer experimental autoimmune encephalomyelitis (widely used as an animal model of MS) in the absence of IL-23 and IL-12, respectively. Plastic Th17 cells are particularly potent mediators of demyelination and axonopathy. In parallel studies, we identified MS patients who consistently mount either IFN-\u03b3\u2013 or IL-17\u2013skewed responses to myelin basic protein over the course of a year. Brain magnetic resonance imaging revealed that patients with mixed IFN-\u03b3 and IL-17 responses have relatively high T1 lesion burden, a measure of permanent axon damage. Our data challenge the dogma that IL-23 and Th17 plasticity are universally required for the development of experimental autoimmune encephalomyelitis. This study definitively demonstrates that autoimmune demyelinating disease can be driven by distinct Th-polarizing factors and effector subsets, underscoring the importance of a customized approach to the pharmaceutical management of MS.<\/jats:p>","DOI":"10.4049\/jimmunol.1501097","type":"journal-article","created":{"date-parts":[[2015,8,4]],"date-time":"2015-08-04T01:50:15Z","timestamp":1438653015000},"page":"2552-2559","source":"Crossref","is-referenced-by-count":71,"title":["Th Cell Diversity in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis"],"prefix":"10.1093","volume":"195","author":[{"given":"Kevin S","family":"Carbajal","sequence":"first","affiliation":[{"name":"Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yevgeniya","family":"Mironova","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, University of Michigan , Ann Arbor, MI 48109"},{"name":"Cellular and Molecular Biology Graduate Program, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin T","family":"Ulrich-Lewis","sequence":"additional","affiliation":[{"name":"Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deven","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather M","family":"Grifka-Walk","sequence":"additional","affiliation":[{"name":"Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan , Ann Arbor, MI 48109"},{"name":"Graduate Program in Immunology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda K","family":"Huber","sequence":"additional","affiliation":[{"name":"Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Shrager","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Anatomy, University of Rochester Medical Center , Rochester, NY 14642"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roman J","family":"Giger","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, University of Michigan , Ann Arbor, MI 48109"},{"name":"Cellular and Molecular Biology Graduate Program, University of Michigan , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin M","family":"Segal","sequence":"additional","affiliation":[{"name":"Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan , Ann Arbor, MI 48109"},{"name":"Graduate Program in Immunology, University of Michigan , Ann Arbor, MI 48109"},{"name":"Neurology Service, VA Ann Arbor Healthcare System , Ann Arbor, MI 48105"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,9,15]]},"reference":[{"key":"2025030704123122700_r1","doi-asserted-by":"crossref","first-page":"137","DOI":"10.3109\/08916939309043888","article-title":"T helper 1 (Th1) functional phenotype of human myelin basic protein-specific T lymphocytes","volume":"15","author":"Voskuhl","year":"1993","journal-title":"Autoimmunity"},{"key":"2025030704123122700_r2","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1007\/s11882-003-0017-6","article-title":"Experimental autoimmune encephalomyelitis: cytokines, effector T cells, and antigen-presenting cells in a prototypical Th1-mediated autoimmune disease","volume":"3","author":"Segal","year":"2003","journal-title":"Curr. Allergy Asthma Rep."},{"key":"2025030704123122700_r3","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1084\/jem.184.2.771","article-title":"IL-12 unmasks latent autoimmune disease in resistant mice","volume":"184","author":"Segal","year":"1996","journal-title":"J. Exp. Med."},{"key":"2025030704123122700_r4","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1084\/jem.20031819","article-title":"Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis","volume":"200","author":"Bettelli","year":"2004","journal-title":"J. Exp. Med."},{"key":"2025030704123122700_r5","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1084\/jem.20041257","article-title":"IL-23 drives a pathogenic T cell population that induces autoimmune inflammation","volume":"201","author":"Langrish","year":"2005","journal-title":"J. Exp. Med."},{"key":"2025030704123122700_r6","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1002\/ana.21748","article-title":"Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis","volume":"66","author":"Kebir","year":"2009","journal-title":"Ann. Neurol."},{"key":"2025030704123122700_r7","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1038\/nature01355","article-title":"Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain","volume":"421","author":"Cua","year":"2003","journal-title":"Nature"},{"key":"2025030704123122700_r8","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.cell.2006.07.035","article-title":"The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells","volume":"126","author":"Ivanov","year":"2006","journal-title":"Cell"},{"key":"2025030704123122700_r9","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1084\/jem.20080159","article-title":"IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition","volume":"205","author":"Kroenke","year":"2008","journal-title":"J. Exp. Med."},{"key":"2025030704123122700_r10","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1038\/nm.2110","article-title":"T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis","volume":"16","author":"Axtell","year":"2010","journal-title":"Nat. Med."},{"key":"2025030704123122700_r11","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.immuni.2008.11.005","article-title":"Late developmental plasticity in the T helper 17 lineage","volume":"30","author":"Lee","year":"2009","journal-title":"Immunity"},{"key":"2025030704123122700_r12","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/ni.1993","article-title":"Fate mapping of IL-17-producing T cells in inflammatory responses","volume":"12","author":"Hirota","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025030704123122700_r13","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.4049\/jimmunol.172.5.2827","article-title":"Compromised humoral and delayed-type hypersensitivity responses in IL-23-deficient mice","volume":"172","author":"Ghilardi","year":"2004","journal-title":"J. Immunol."},{"key":"2025030704123122700_r14","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.nbd.2014.05.015","article-title":"DLK-dependent signaling is important for somal but not axonal degeneration of retinal ganglion cells following axonal injury","volume":"69","author":"Fernandes","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"2025030704123122700_r15","doi-asserted-by":"crossref","first-page":"17736","DOI":"10.1523\/JNEUROSCI.1482-11.2011","article-title":"Congenital CNS hypomyelination in the Fig4 null mouse is rescued by neuronal expression of the PI(3,5)P(2) phosphatase Fig4","volume":"31","author":"Winters","year":"2011","journal-title":"J. Neurosci."},{"key":"2025030704123122700_r16","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1002\/ana.22366","article-title":"Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria","volume":"69","author":"Polman","year":"2011","journal-title":"Ann. Neurol."},{"key":"2025030704123122700_r17","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1212\/WNL.0000000000000908","article-title":"Dysregulation of the IL-23\/IL-17 axis and myeloid factors in secondary progressive MS","volume":"83","author":"Huber","year":"2014","journal-title":"Neurology"},{"key":"2025030704123122700_r18","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1002\/eji.201040489","article-title":"EAE mediated by a non-IFN-\u03b3\/non-IL-17 pathway","volume":"40","author":"Kroenke","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"2025030704123122700_r19","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/ni.2027","article-title":"ROR\u03b3t drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation","volume":"12","author":"Codarri","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025030704123122700_r20","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/ni.2031","article-title":"The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF","volume":"12","author":"El-Behi","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025030704123122700_r21","doi-asserted-by":"crossref","first-page":"39","DOI":"10.4049\/jimmunol.178.1.39","article-title":"GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis","volume":"178","author":"Ponomarev","year":"2007","journal-title":"J. Immunol."},{"key":"2025030704123122700_r22","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1056\/NEJM199801293380502","article-title":"Axonal transection in the lesions of multiple sclerosis","volume":"338","author":"Trapp","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"2025030704123122700_r23","doi-asserted-by":"crossref","first-page":"14965","DOI":"10.1523\/JNEUROSCI.3794-09.2009","article-title":"Initiation and progression of axonopathy in experimental autoimmune encephalomyelitis","volume":"29","author":"Soulika","year":"2009","journal-title":"J. Neurosci."},{"key":"2025030704123122700_r24","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1093\/brain\/121.8.1469","article-title":"Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study","volume":"121","author":"De Stefano","year":"1998","journal-title":"Brain"},{"key":"2025030704123122700_r25","doi-asserted-by":"crossref","first-page":"3750","DOI":"10.4049\/jimmunol.181.6.3750","article-title":"Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis","volume":"181","author":"O\u2019Connor","year":"2008","journal-title":"J. Immunol."},{"key":"2025030704123122700_r26","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1172\/JCI200319079","article-title":"IL-23 produced by CNS-resident cells controls T cell encephalitogenicity during the effector phase of experimental autoimmune encephalomyelitis","volume":"112","author":"Becher","year":"2003","journal-title":"J. Clin. Invest."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/195\/6\/2552\/61503943\/1501097.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/195\/6\/2552\/61503943\/1501097.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T04:27:33Z","timestamp":1741321653000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/195\/6\/2552\/7961478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,9]]},"references-count":26,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2015,9,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1501097","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,9]]},"published":{"date-parts":[[2015,9]]}}}