TY - JOUR
T1 - T cell response to myelin basic protein in the context of the multiple sclerosis-associated HLA-DR15 haplotype
T2 - Peptide binding, immunodominance and effector functions of T cells
AU - Vergelli, M.
AU - Kalbus, M.
AU - Rojo, S. C.
AU - Hemmer, B.
AU - Kalbacher, H.
AU - Tranquill, L.
AU - Beck, H.
AU - McFarland, H. F.
AU - De Mars, R.
AU - Long, E. O.
AU - Martin, R.
PY - 1997/8
Y1 - 1997/8
N2 - In this study, we evaluated the role of the two functional HLA-DR heterodimers, DR2a (DR α paired with the β chain encoded by DRB5(*) 0101) and DR2b (DR α paired with the β 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.
AB - In this study, we evaluated the role of the two functional HLA-DR heterodimers, DR2a (DR α paired with the β chain encoded by DRB5(*) 0101) and DR2b (DR α paired with the β 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.
KW - HLA binding
KW - HLA-DR15
KW - Immunodominance
KW - MBP
KW - Multiple sclerosis
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U2 - 10.1016/S0165-5728(97)00075-1
DO - 10.1016/S0165-5728(97)00075-1
M3 - Article
C2 - 9258250
AN - SCOPUS:18544397838
SN - 0165-5728
VL - 77
SP - 195
EP - 203
JO - Journal of Neuroimmunology
JF - Journal of Neuroimmunology
IS - 2
ER -