title: Immunodominant T-cell epitopes of MOG reside in its transmembrane and cytoplasmic domains in EAE.
abstract: OBJECTIVE
  Studies evaluating T-cell recognition of myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis (MS) and its model, experimental autoimmune encephalomyelitis (EAE), have focused mostly on its 117 amino acid (aa) extracellular domain, especially peptide (p) 35-55. We characterized T-cell responses to the entire 218 aa MOG sequence, including its transmembrane and cytoplasmic domains.
  
  
  METHODS
  T-cell recognition in mice was examined using overlapping peptides and intact full-length mouse MOG. EAE was evaluated by peptide immunization and by adoptive transfer of MOG epitope-specific T cells. Frequency of epitope-specific T cells was examined by ELISPOT.
  
  
  RESULTS
  Three T-cell determinants of MOG were discovered in its transmembrane and cytoplasmic domains, p119-132, p181-195, and p186-200. Transmembrane MOG p119-132 induced clinical EAE, CNS inflammation, and demyelination as potently as p35-55 in C57BL/6 mice and other H-2(b) strains. p119-128 contained its minimal encephalitogenic epitope. p119-132 did not cause disease in EAE-susceptible non-H-2(b) strains, including Biozzi, NOD, and PL/J. MOG p119-132-specific T cells produced Th1 and Th17 cytokines and transferred EAE to wild-type recipient mice. After immunization with full-length MOG, a significantly higher frequency of MOG-reactive T cells responded to p119-132 than to p35-55, demonstrating that p119-132 is an immunodominant encephalitogenic epitope. MOG p181-195 did not cause EAE, and MOG p181-195-specific T cells could not transfer EAE into wild-type or highly susceptible T- and B-cell-deficient mice.
  
  
  CONCLUSIONS
  Transmembrane and cytoplasmic domains of MOG contain immunodominant T-cell epitopes in EAE. A CNS autoantigen can also contain nonpathogenic stimulatory T-cell epitopes. Recognition that a myelin antigen contains multiple encephalitogenic and nonencephalitogenic determinants may have implications for therapeutic development in MS.
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Shetty
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Sheena G
authors.initials: SG
authors.lastname: Gupta
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Michel
authors.initials: M
authors.lastname: Varrin-Doyer
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Weber
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Prod'homme
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Molnarfi
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Niannian
authors.initials: N
authors.lastname: Ji
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Nelson
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Patarroyo
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schulze-Topphoff
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Fogal
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Forsthuber
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Claude C A
authors.initials: CC
authors.lastname: Bernard
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Slavin
authors.affiliation: Department of Neurology and Program in Immunology (A.S., S.G.G., M.V.-D., T.P., N.M., P.A.N., J.C.P., U.S.-T., S.S.Z.), University of California, San Francisco; Department of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg-August University, Göttingen, Germany; Department of Immunology (N.J., T.F.), University of Texas at San Antonio; Boehringer Ingelheim (S.E.F., A.J.S.), Ridgefield, CT; Department of Pathology (R.A.S.), Stanford University, Stanford, CA; and Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. S.G.G. is currently at the Institute for Immunity Transplantation and Infection, Stanford University, Stanford, CA. T.P. is currently at Momenta Pharmaceuticals, Cambridge, MA. N.M. is currently at the Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospital and the Department of Pathology and Immunology, Geneva Faculty of Medicine, University Medical Center, Geneva, Switzerland. J.C.P. is currently at Pfizer, Inc., Cambridge, MA.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Zamvil