title: Highly polarized Th17 cells induce EAE via a T-bet independent mechanism.
abstract: In the MOG35-55 induced EAE model, autoreactive Th17 cells that accumulate in the central nervous system acquire Th1 characteristics via a T-bet dependent mechanism. It remains to be determined whether Th17 plasticity and encephalitogenicity are causally related to each other. Here, we show that IL-23 polarized T-bet(-/-) Th17 cells are unimpaired in either activation or proliferation, and induce higher quantities of the chemokines RANTES and CXCL2 than WT Th17 cells. Unlike their WT counterparts, T-bet(-/-) Th17 cells retain an IL-17(hi) IFN-γ(neg-lo) cytokine profile following adoptive transfer into syngeneic hosts. This population of highly polarized Th17 effectors is capable of mediating EAE, albeit with a milder clinical course. It has previously been reported that the signature Th1 and Th17 effector cytokines, IFN-γ and IL-17, are dispensable for the development of autoimmune demyelinating disease. The current study demonstrates that the "master regulator" transcription factor, T-bet, is also not universally required for encephalitogenicity. Our results contribute to a growing body of data showing heterogeneity of myelin-reactive T cells and the independent mechanisms they employ to inflict damage to central nervous system tissues, complicating the search for therapeutic targets relevant across the spectrum of individuals with multiple sclerosis.
authors.affiliation: Holtom-Garrett Program in Neuroimmunology and Multiple Sclerosis Center, Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Grifka-Walk
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lalor
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Segal
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D016764:Cell Polarity / Q000276:immunology; D049109:Cell Proliferation; D002490:Central Nervous System / Q000276:immunology; D018946:Chemokine CCL5 / Q000096:biosynthesis; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D053759:Interleukin-23; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D018946:Chemokine CCL5; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D004268:DNA-Binding Proteins; D020381:Interleukin-17; D053759:Interleukin-23; C499308:Rag2 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma
keywords: Experimental autoimmune encephalomyelitis; Multiple sclerosis; Neuroimmunology; T-bet; Th17 cells