title: IL-1-induced Bhlhe40 identifies pathogenic T helper cells in a model of autoimmune neuroinflammation.
abstract: The features that define autoreactive T helper (Th) cell pathogenicity remain obscure. We have previously shown that Th cells require the transcription factor Bhlhe40 to mediate experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Here, using Bhlhe40 reporter mice and analyzing both polyclonal and TCR transgenic Th cells, we found that Bhlhe40 expression was heterogeneous after EAE induction, with Bhlhe40-expressing cells displaying marked production of IFN-γ, IL-17A, and granulocyte-macrophage colony-stimulating factor. In adoptive transfer EAE models, Bhlhe40-deficient Th1 and Th17 cells were both nonencephalitogenic. Pertussis toxin (PTX), a classical co-adjuvant for actively induced EAE, promoted IL-1β production by myeloid cells in the draining lymph node and served as a strong stimulus for Bhlhe40 expression in Th cells. Furthermore, PTX co-adjuvanticity was Bhlhe40 dependent. IL-1β induced Bhlhe40 expression in polarized Th17 cells, and Bhlhe40-expressing cells exhibited an encephalitogenic transcriptional signature. In vivo, IL-1R signaling was required for full Bhlhe40 expression by Th cells after immunization. Overall, we demonstrate that Bhlhe40 expression identifies encephalitogenic Th cells and defines a PTX-IL-1-Bhlhe40 pathway active in EAE.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Tara R
authors.initials: TR
authors.lastname: Bradstreet
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Schwarzkopf
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Nicholas N
authors.initials: NN
authors.lastname: Jarjour
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Chun
authors.initials: C
authors.lastname: Chou
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Angela S
authors.initials: AS
authors.lastname: Archambault
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Julia
authors.initials: J
authors.lastname: Sim
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Zinselmeyer
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Carrero
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110 Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Wu
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Reshma
authors.initials: R
authors.lastname: Taneja
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Artyomov
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: John H
authors.initials: JH
authors.lastname: Russell
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 bedelson@path.wustl.edu.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Edelson
mesh_terms: D000276:Adjuvants, Immunologic; D019264:Adoptive Transfer; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D037342:Pertussis Toxin / Q000276:immunology; D053573:Receptors, Interleukin-1 Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology
chemical_list: D000276:Adjuvants, Immunologic; D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D016753:Interleukin-10; D053583:Interleukin-1beta; D037342:Pertussis Toxin; D053573:Receptors, Interleukin-1 Type I; C491539:Bhlhe40 protein, mouse; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; C583355:IL1R1 protein, mouse
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