CD8 T cell responses to myelin oligodendrocyte glycoprotein-derived peptides in humanized HLA-A*0201-transgenic mice.
Multiple sclerosis (MS) is a demyelinating inflammatory disease of the CNS. Though originally believed to be CD4-mediated, additional immune effector mechanisms, including myelin-specific CD8(+) T cells, are now proposed to participate in the pathophysiology of MS. To study the immunologic and encephalitogenic behavior of HLA-A*0201-binding myelin-derived epitopes in vivo, we used a humanized HLA-A*0201-transgenic mouse model. Eight HLA-A*0201-binding peptides derived from myelin oligodendrocyte glycoprotein (MOG), an immunodominant myelin self-Ag, were identified in silico. After establishing their relative affinity for HLA-A*0201 and their capacity to form stable complexes with HLA-A*0201 in vitro, their immunological characteristics were studied in HLA-A*0201-transgenic mice. Five MOG peptides, which bound stably to HLA-A*0201 exhibited strong immunogenicity by inducing a sizeable MOG-specific HLA-A*0201-restricted CD8(+) T cell response in vivo. Of these five candidate epitopes, four were processed by MOG-transfected RMA target cells and two peptides proved immunodominant in vivo in response to a plasmid-encoding native full-length MOG. One of the immunodominant MOG peptides (MOG(181)) generated a cytotoxic CD8(+) T cell response able to aggravate CD4(+)-mediated EAE. Therefore, this detailed in vivo characterization provides a hierarchy of candidate epitopes for MOG-specific CD8(+) T cell responses in HLA-A*0201 MS patients identifying the encephalitogenic MOG(181) epitope as a primary candidate.
Mars
Lennart T
LT
Institut National de la Santé et de la Recherche Médicale, Unité 563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
Bauer
Jan
J
Gross
David A
DA
Bucciarelli
Florence
F
Firat
Huseyin
H
Hudrisier
Denis
D
Lemonnier
François
F
Kosmatopoulos
Kostas
K
Liblau
Roland S
RS
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006023:Glycoproteins / Q000008:administration & dosage* / Q000276:immunology* / Q000378:metabolism; D015234:HLA-A Antigens / Q000235:genetics* / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000276:immunology
D006023:Glycoproteins; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D063308:Myelin-Oligodendrocyte Glycoprotein; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55)