title: Bispecificity for myelin and neuronal self-antigens is a common feature of CD4 T cells in C57BL/6 mice.
abstract: The recognition of multiple ligands by a single TCR is an intrinsic feature of T cell biology, with important consequences for physiological and pathological processes. Polyspecific T cells targeting distinct self-antigens have been identified in healthy individuals as well as in the context of autoimmunity. We have previously shown that the 2D2 TCR recognizes the myelin oligodendrocyte glycoprotein epitope (MOG)35-55 as well as an epitope within the axonal protein neurofilament medium (NF-M15-35) in H-2(b) mice. In this study, we assess whether this cross-reactivity is a common feature of the MOG35-55-specific T cell response. To this end, we analyzed the CD4 T cell response of MOG35-55-immunized C57BL/6 mice for cross-reactivity with NF-M15-35. Using Ag recall responses, we established that an important proportion of MOG35-55-specific CD4 T cells also responded to NF-M15-35 in all mice tested. To study the clonality of this response, we analyzed 22 MOG35-55-specific T cell hybridomas expressing distinct TCR. Seven hybridomas were found to cross-react with NF-M15-35. Using an alanine scan of NF-M18-30 and an in silico predictive model, we dissected the molecular basis of cross-reactivity between MOG35-55 and NF-M15-35. We established that NF-M F24, R26, and V27 proved important TCR contacts. Strikingly, the identified TCR contacts are conserved within MOG38-50. Our data indicate that due to linear sequence homology, part of the MOG35-55-specific T cell repertoire of all C57BL/6 mice also recognizes NF-M15-35, with potential implications for CNS autoimmunity.
authors.affiliation: INSERM, U1043, Toulouse F-31300, France; Centre National de la Recherche Scientifique, U5282, Toulouse F-31300, France; Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse F-31300, France;
authors.forename: Liliana E
authors.initials: LE
authors.lastname: Lucca
authors.affiliation: INSERM, U1043, Toulouse F-31300, France; Centre National de la Recherche Scientifique, U5282, Toulouse F-31300, France; Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse F-31300, France;
authors.forename: Sabine
authors.initials: S
authors.lastname: Desbois
authors.affiliation: INSERM, U1043, Toulouse F-31300, France; Centre National de la Recherche Scientifique, U5282, Toulouse F-31300, France; Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse F-31300, France;
authors.forename: Abdulraouf
authors.initials: A
authors.lastname: Ramadan
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Chemical Support, Weizmann Institute of Science, Rehovot 7610001, Israel;
authors.forename: Avraham
authors.initials: A
authors.lastname: Ben-Nun
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Chemical Support, Weizmann Institute of Science, Rehovot 7610001, Israel;
authors.forename: Miriam
authors.initials: M
authors.lastname: Eisenstein
authors.affiliation: INSERM, U1043, Toulouse F-31300, France; Centre National de la Recherche Scientifique, U5282, Toulouse F-31300, France; Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse F-31300, France;
authors.forename: Nadège
authors.initials: N
authors.lastname: Carrié
authors.affiliation: INSERM, U1043, Toulouse F-31300, France; Centre National de la Recherche Scientifique, U5282, Toulouse F-31300, France; Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse F-31300, France;
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Guéry
authors.affiliation: La Jolla Institute for Allergy and Immunology, San Diego, CA 92109;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors.forename: Phuong
authors.initials: P
authors.lastname: Nguyen
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors.forename: Terrence L
authors.initials: TL
authors.lastname: Geiger
authors.affiliation: INSERM, U1043, Toulouse F-31300, France; Centre National de la Recherche Scientifique, U5282, Toulouse F-31300, France; Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse F-31300, France;
authors.forename: Lennart T
authors.initials: LT
authors.lastname: Mars
authors.affiliation: INSERM, U1043, Toulouse F-31300, France; Centre National de la Recherche Scientifique, U5282, Toulouse F-31300, France; Centre de Physiopathologie Toulouse-Purpan, Université Toulouse 3, Toulouse F-31300, France; Département d'Immunologie, Centre Hospitalier Universitaire Toulouse, Hôpital Purpan, Toulouse F-31300, France roland.liblau@inserm.fr.
authors.forename: Roland S
authors.initials: RS
authors.lastname: Liblau
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003429:Cross Reactions / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000235:genetics / Q000276:immunology*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000235:genetics / Q000276:immunology*; D016900:Neurofilament Proteins / Q000235:genetics / Q000276:immunology*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D011946:Receptors, Antigen / Q000235:genetics / Q000276:immunology*
chemical_list: D001324:Autoantigens; D063308:Myelin-Oligodendrocyte Glycoprotein; D016900:Neurofilament Proteins; D010446:Peptide Fragments; D011946:Receptors, Antigen; C445081:myelin oligodendrocyte glycoprotein (35-55); C061195:neurofilament protein M