T Cell Epitope 119-132, but Not 35-55, Is the Immunodominant Encephalitogenic Determinant of the CNS Autoantigen, Myelin Oligodendrocyte Glycoprotein (P05.118)

Abstract

Objective: To evaluate native full-length MOG for novel T cell epitopes. Background Amino acid (aa) residues 35-55 within the extracellular domain 1-117 of myelin oligodendrocyte glycoprotein (MOG) contain its only known encephalitogenic T cell determinant for C57BL/6 (H-2^b) mice, a strain frequently studied in the multiple sclerosis (MS) model, experimental autoimmune encephalomyelitis (EAE). Based upon studies showing that processing of native MOG is required for presentation of 35-55, we predicted that MOG contains additional T cell epitopes. Design/Methods: C57BL/6 mice were immunized with full-length (218 aa) murine (self) MOG or overlapping peptides encompassing its entire sequence in complete Freund9s adjuvant. Proliferation was measured by 3^H-thymidine incorporation. ELISPOT was used to measure frequency of epitope-specific IFN-γ-producing T cells that were generated by in vivo priming with full-length MOG. Results: Three novel T cell epitopes were discovered, an encephalitogenic determinant within transmembrane domain residues 119-132, and two discrete nonencephalitogenic determinants, p181-195 and p186-200, in the cytoplasmic domain. Clinical EAE, CNS inflammation and demyelination induced by p119-132 were equal, or greater, in severity than with p35-55. T cell recognition of MOG p119-132 was restricted by MHC II (I-A^b) molecules and p119-132 induced EAE in other H-2^b strains, but not in mice of other haplotypes. MOG p119-132-primed T cells, which produced higher levels of pathogenic Th1 and Th17 cytokines than p35-55-primed T cells, adoptively transferred EAE to naive recipients. Frequency of T cells that responded to p119-132 after immunization with full-length MOG was greater than to p35-55 or the non-encephalitogenic determinants, demonstrating that p119-132 is the immunodominant determinant. Conclusions: MOG p119-132, not p35-55, is the immunodominant encephalitogenic determinant of MOG. Not all T cell epitopes of a self antigen are pathogenic. Recognizing that MOG contains multiple encephalitogenic and non-encephalitogenic determinants permits testing tolerogenic approaches that target individual non-pathogenic or pathogenic T cell epitopes. Supported by: NIH and Boehringer-Ingelheim. Disclosure: Dr. Shetty has received research support from Boehringer Ingelheim. Dr. Gupta has received research support from Boehringer Ingelheim Pharmaceuticals, Inc. Dr. Weber has received personal compensation for activities with Hoffmann-LaRoche, Genentech, Inc., Novartis, Bayer Pharmaceuticals Corporation, Merck Serono, Biogen Idec and Teva Neuroscience as a speaker and/or participant on an advisory board. Dr. Weber has received research support from Teva Neuroscience. Dr. Molnarfi has nothing to disclose. Dr. Forsthuber has received research support from the National Institutes of Health. Dr. Sobel has received research support from the NIH. Dr. Bernard has nothing to disclose. Dr. Slavin has received personal compensation for activities with Boehringer Ingelheim as an employee. Dr. Slavin holds stock and/or stock options in Boehringer Ingelheim. Dr. Slavin has received research support from Boehringer Ingelheim. Dr. Zamvil has received personal compensation for activities with Biogen Idec, Teva Neuroscience and EMD Serono-Pfizer. Dr. Zamvil has received research support from the National Institutes of Health, National Multiple Sclerosis Society, the Maisin Foundation, the Guthy Jackson Charitable Foundation, Teva Neuroscience, and Boehringer Ingelheim Pharmaceuticals, Inc.