T cell response to myelin basic protein in the context of the multiple sclerosis-associated HLA-DR15 haplotype: peptide binding, immunodominance and effector functions of T cells.
In this study, we evaluated the role of the two functional HLA-DR heterodimers, DR2a (DR alpha paired with the beta chain encoded by DRB5*0101) and DR2b (DR alpha paired with the beta chain encoded by DRB1*1501), that are coexpressed in the multiple sclerosis (MS)-associated haplotype HLA-DR15 Dw2, in presenting myelin basic protein (MBP) peptides to MBP-specific T cell lines (TCL). Our results show that both HLA-DR molecules serve as restriction elements for HLA-DR15-restricted TCL. Slightly higher numbers of TCL use DR2a as restriction element, and the epitopes contained in the immunodominant C-terminal region (131-159) are uniquely restricted by DR2a. The immunodominant middle epitope (81-99) is recognized in the context of both DR2a and DR2b, but this specificity strongly dominates the DR2b-restricted T cell response. Overall, immunodominance in the MBP-specific T cell response correlated well with peptide binding to DR2a or DR2b, demonstrating that the affinity of MHC-peptide interactions is important for shaping the T cell response to this autoantigen. Furthermore, we show that binding of the middle MBP peptide to HLA-DR15 molecules prevents cleavage by cathepsin D, a protease abundantly found in endosomal processing compartments, and thus contributes to its immunodominance. Surprisingly, the restriction element employed by MBP-specific T cell clones influenced the effector function (i.e., cytotoxic activity) of T cells irrespective of their peptide fine specificity.
Vergelli
M
M
Neuroimmunology Branch, NINDS, NIH, Bethesda, MD 20892-1400, USA.
Kalbus
M
M
Rojo
S C
SC
Hemmer
B
B
Kalbacher
H
H
Tranquill
L
L
Beck
H
H
McFarland
H F
HF
De Mars
R
R
Long
E O
EO
Martin
R
R
D000483:Alleles; D000595:Amino Acid Sequence; D002402:Cathepsin D / Q000378:metabolism; D002460:Cell Line; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D006684:HLA-DR Antigens / Q000235:genetics* / Q000378:metabolism; D059810:HLA-DR Serological Subtypes; D015802:HLA-DR2 Antigen / Q000235:genetics / Q000378:metabolism; D006239:Haplotypes / Q000276:immunology*; D006801:Humans; D006868:Hydrolysis; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology*; D004676:Myelin Basic Protein / Q000276:immunology* / Q000378:metabolism; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C106559:HLA-DR15 antigen; D015802:HLA-DR2 Antigen; D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D010455:Peptides; D002402:Cathepsin D