title: Immunodominant T cell determinants of aquaporin-4, the autoantigen associated with neuromyelitis optica.
abstract: Autoantibodies that target the water channel aquaporin-4 (AQP4) in neuromyelitis optica (NMO) are IgG1, a T cell-dependent Ig subclass. However, a role for AQP4-specific T cells in this CNS inflammatory disease is not known. To evaluate their potential role in CNS autoimmunity, we have identified and characterized T cells that respond to AQP4 in C57BL/6 and SJL/J mice, two strains that are commonly studied in models of CNS inflammatory diseases. Mice were immunized with either overlapping peptides or intact hAQP4 protein encompassing the entire 323 amino acid sequence. T cell determinants identified from examination of the AQP4 peptide (p) library were located within AQP4 p21-40, p91-110, p101-120, p166-180, p231-250 and p261-280 in C57BL/6 mice, and within p11-30, p21-40, p101-120, p126-140 and p261-280 in SJL/J mice. AQP4-specific T cells were CD4+ and MHC II-restricted. In recall responses to immunization with intact AQP4, T cells responded primarily to p21-40, indicating this region contains the immunodominant T cell epitope(s) for both strains. AQP4 p21-40-primed T cells secreted both IFN-γ and IL-17. The core immunodominant AQP4 21-40 T cell determinant was mapped to residues 24-35 in C57BL/6 mice and 23-35 in SJL/J mice. Our identification of the AQP4 T cell determinants and characterization of its immunodominant determinant should permit investigators to evaluate the role of AQP4-specific T cells in vivo and to develop AQP4-targeted murine NMO models.
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Nelson
authors.forename: Mojgan
authors.initials: M
authors.lastname: Khodadoust
authors.forename: Thomas
authors.initials: T
authors.lastname: Prodhomme
authors.forename: Collin
authors.initials: C
authors.lastname: Spencer
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Patarroyo
authors.forename: Michel
authors.initials: M
authors.lastname: Varrin-Doyer
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Ho
authors.forename: Robert M
authors.initials: RM
authors.lastname: Stroud
authors.forename: Scott S
authors.initials: SS
authors.lastname: Zamvil
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051401:Aquaporin 4 / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007114:Immunization; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009471:Neuromyelitis Optica / Q000175:diagnosis / Q000276:immunology*; D010455:Peptides / Q000737:chemistry / Q000276:immunology
chemical_list: D051401:Aquaporin 4; D001323:Autoantibodies; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D020381:Interleukin-17; D010455:Peptides; D007371:Interferon-gamma