title: In situ expansion of T cells that recognize distinct self-antigens sustains autoimmunity in the CNS.
abstract: Polyspecific T cells recognizing multiple distinct self-antigens have been identified in multiple sclerosis and other organ-specific autoimmune diseases, but their pathophysiological relevance remains undetermined. Using a mouse model of multiple sclerosis, we show that autoimmune encephalomyelitis induction is strictly dependent on reactivation of pathogenic T cells by a peptide (35-55) derived from myelin oligodendrocyte glycoprotein (MOG). This disease-inducing response wanes after onset. Strikingly, the progression of disease is driven by the in situ activation and expansion of a minority of MOG35-55-specific T cells that also recognize neurofilament-medium (NF-M)15-35, an intermediate filament protein expressed in neurons. This mobilization of bispecific T cells is critical for disease progression as adoptive transfer of NF-M15-35/MOG35-55 bispecific T cell lines caused full-blown disease in wild-type but not NF-M-deficient recipients. Moreover, specific tolerance through injection of NF-M15-35 peptide at the peak of disease halted experimental autoimmune encephalomyelitis progression. Our findings highlight the importance of polyspecific autoreactive T cells in the aggravation and perpetuation of central nervous system autoimmunity.
authors.affiliation: INSERM UMR1043, Toulouse, F-31300, France CNRS, U5282, Toulouse, F-31300, France Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France.
authors.forename: Abdulraouf
authors.initials: A
authors.lastname: Ramadan
authors.affiliation: INSERM UMR1043, Toulouse, F-31300, France CNRS, U5282, Toulouse, F-31300, France Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France.
authors.forename: Liliana E
authors.initials: LE
authors.lastname: Lucca
authors.affiliation: INSERM UMR1043, Toulouse, F-31300, France CNRS, U5282, Toulouse, F-31300, France Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Carrié
authors.affiliation: INSERM UMR1043, Toulouse, F-31300, France CNRS, U5282, Toulouse, F-31300, France Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Desbois
authors.affiliation: INSERM UMR1043, Toulouse, F-31300, France CNRS, U5282, Toulouse, F-31300, France Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France.
authors.forename: Pierre-Paul
authors.initials: PP
authors.lastname: Axisa
authors.affiliation: INSERM UMR1043, Toulouse, F-31300, France CNRS, U5282, Toulouse, F-31300, France Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Hayder
authors.affiliation: Center for Brain Research, Department of Neuroimmunology, Medical University of Vienna, Vienna, Austria.
authors.forename: Jan
authors.initials: J
authors.lastname: Bauer
authors.affiliation: INSERM UMR1043, Toulouse, F-31300, France CNRS, U5282, Toulouse, F-31300, France Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France.
authors.forename: Roland S
authors.initials: RS
authors.lastname: Liblau
authors.affiliation: INSERM UMR1043, Toulouse, F-31300, France CNRS, U5282, Toulouse, F-31300, France Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France INSERM UMR995, LIRIC, F-59000 Lille, France Université de Lille, centre d'excellence LICEND and FHU IMMINeNT, F-59000 Lille, France Lennart.Mars@inserm.fr.
authors.forename: Lennart T
authors.initials: LT
authors.lastname: Mars
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D002478:Cells, Cultured; D002490:Central Nervous System / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001324:Autoantigens; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55)
keywords: T cells; TCR; autoimmune disease; central nervous system; experimental autoimmune encephalomyelitis