title: Myelin oligodendrocyte glycoprotein induces incomplete tolerance of CD4(+) T cells specific for both a myelin and a neuronal self-antigen in mice.
abstract: T-cell polyspecificity, predicting that individual T cells recognize a continuum of related ligands, implies that multiple antigens can tolerize T cells specific for a given self-antigen. We previously showed in C57BL/6 mice that part of the CD4(+) T-cell repertoire specific for myelin oligodendrocyte glycoprotein (MOG) 35-55 also recognizes the neuronal antigen neurofilament medium (NF-M) 15-35. Such bi-specific CD4(+) T cells are frequent and produce inflammatory cytokines after stimulation. Since T cells recognizing two self-antigens would be expected to be tolerized more efficiently, this finding prompted us to study how polyspecificity impacts tolerance. We found that similar to MOG, NF-M is expressed in the thymus by medullary thymic epithelial cells, a tolerogenic population. Nevertheless, the frequency, phenotype, and capacity to transfer experimental autoimmune encephalomyelitis (EAE) of MOG35-55 -reactive CD4(+) T cells were increased in MOG-deficient but not in NF-M-deficient mice. We found that presentation of NF-M15-35 by I-A(b) on dendritic cells is of short duration, suggesting unstable MHC class II binding. Consistently, introducing an MHC-anchoring residue into NF-M15-35 (NF-M15-35 T20Y) increased its immunogenicity, activating a repertoire able to induce EAE. Our results show that in C57BL/6 mice bi-specific encephalitogenic T cells manage to escape tolerization due to inefficient exposure to two self-antigens.
authors.affiliation: INSERM, U1043, Toulouse, France.|Centre National de la Recherche Scientifique, U5282, Toulouse, France.|Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse, France.
authors.forename: Liliana E
authors.initials: LE
authors.lastname: Lucca
authors.affiliation: INSERM, U1043, Toulouse, France.|Centre National de la Recherche Scientifique, U5282, Toulouse, France.|Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse, France.
authors.forename: Pierre-Paul
authors.initials: PP
authors.lastname: Axisa
authors.affiliation: INSERM, U1043, Toulouse, France.|Centre National de la Recherche Scientifique, U5282, Toulouse, France.|Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse, France.
authors.forename: Meryem
authors.initials: M
authors.lastname: Aloulou
authors.affiliation: INSERM, U1043, Toulouse, France.|Centre National de la Recherche Scientifique, U5282, Toulouse, France.|Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse, France.
authors.forename: Corine
authors.initials: C
authors.lastname: Perals
authors.affiliation: INSERM, U1043, Toulouse, France.|Centre National de la Recherche Scientifique, U5282, Toulouse, France.|Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse, France.
authors.forename: Abdulraouf
authors.initials: A
authors.lastname: Ramadan
authors.affiliation: INSERM, U1043, Toulouse, France.|Centre National de la Recherche Scientifique, U5282, Toulouse, France.|Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Rufas
authors.affiliation: Developmental Immunobiology, Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Kyewski
authors.affiliation: Developmental Immunobiology, Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Derbinski
authors.affiliation: INSERM, U1043, Toulouse, France.|Centre National de la Recherche Scientifique, U5282, Toulouse, France.|Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fazilleau
authors.affiliation: INSERM, U1043, Toulouse, France.|Centre National de la Recherche Scientifique, U5282, Toulouse, France.|Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse, France.
authors.forename: Lennart T
authors.initials: LT
authors.lastname: Mars
authors.affiliation: INSERM, U1043, Toulouse, France. roland.liblau@inserm.fr.|Centre National de la Recherche Scientifique, U5282, Toulouse, France. roland.liblau@inserm.fr.|Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse, France. roland.liblau@inserm.fr.|CHU Toulouse, Département d'Immunologie, Toulouse, France. roland.liblau@inserm.fr.
authors.forename: Roland S
authors.initials: RS
authors.lastname: Liblau
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D007108:Immune Tolerance; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000235:genetics / Q000276:immunology*; D016900:Neurofilament Proteins / Q000235:genetics; D009474:Neurons / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism
chemical_list: D001324:Autoantigens; D016207:Cytokines; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D016900:Neurofilament Proteins; D012333:RNA, Messenger; C061195:neurofilament protein M
keywords: Autoimmunity; Central nervous system; Polyspecificity; Tolerance; T cell