Increased CD8+ cytotoxic T cell responses to myelin basic protein in multiple sclerosis.
Autoreactive T cells of CD4 and CD8 subsets recognizing myelin basic protein (MBP), a candidate myelin autoantigen, are thought to contribute to and play distinct roles in the pathogenesis of multiple sclerosis (MS). In this study we identified four MBP-derived peptides that had high binding affinity to HLA-A2 and HLA-A24 and characterized the CD8(+) T cell responses and their functional properties in patients with MS. There were significantly increased CD8(+) T cell responses to 9-mer MBP peptides, in particular MBP(111-119) and MBP(87-95) peptides that had high binding affinity to HLA-A2, in patients with MS compared with healthy individuals. The resulting CD8(+) T cell lines were of the Th1 phenotype, producing TNF-alpha and IFN-gamma and belonged to a CD45RA(-)/CD45RO(+) memory T cell subset. Further characterization indicated that the CD8(+) T cell lines obtained were stained with MHC class I tetramer (HLA-A2/MBP(111-119)) and exhibited specific cytotoxicity toward autologous target cells pulsed with MBP-derived peptides in the context of MHC class I molecules. These cytotoxic CD8(+) T cell lines derived from MS patients recognized endogenously processed MBP and lysed COS cells transfected with genes encoding MBP and HLA-A2. These findings support the potential role of CD8(+) CTLs recognizing MBP in the injury of oligodendrocytes expressing both MHC class I molecules and MBP.
Zang
Ying C Q
YC
Multiple Sclerosis Research Unit, Department of Neurology and Baylor Multiple Sclerosis Center, Baylor College of Medicine, Houston, TX 77030, USA. yzang@bcm.tmc.edu
Li
Sufang
S
Rivera
Victor M
VM
Hong
Jian
J
Robinson
Rachel R
RR
Breitbach
Wini T
WT
Killian
James
J
Zhang
Jingwu Z
JZ
D000328:Adult; D017951:Antigen Presentation; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic; D005260:Female; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology*; D004676:Myelin Basic Protein / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D001324:Autoantigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D004676:Myelin Basic Protein; D010446:Peptide Fragments