T cell recognition motifs of an immunodominant peptide of myelin basic protein in patients with multiple sclerosis: structural requirements and clinical implications.
Myelin basic protein (MBP)-reactive T cells may play an important role in the pathogenesis of multiple sclerosis (MS). The T cell response to the 83-99 region of MBP represents a dominant autoreactive response to MBP in MS patients of DR2 haplotype. In this study, a large panel of DR2- and DR4-restricted T cell clones specific for the MBP83-99 peptide were examined for the recognition motifs and structural requirements for antigen recognition using alanine-substituted peptides. Our study revealed that although the recognition motifs of the T cell clones were diverse, the TCR contact residues within the 83-99 region of MBP were highly conserved. Two central residues (Phe90 and Lys91) served as the critical TCR contact points for both DR2- and DR4-restricted T cell clones. Single alanine substitution at residue 90 or residue 91 abolished the responses of 81-95 % of the T cell clones while a double alanine substitution rendered all T cell clones unresponsive. It was also demonstrated in this study that the substituted peptides altered the cytokine profile of some, but not all, T cell clones. Some MBP83-99-specific T cell clones were able to sustain alanine substitutions and were susceptible to activation by microbial antigens. The study has an important implication in designing a peptide-based therapy for MS.
Kozovska
M
M
Department of Neurology and Baylor/Methodist International Multiple Sclerosis Center, Baylor College of Medicine, Houston, TX 77030, USA.
Zang
Y C
YC
Aebischer
I
I
Lnu
S
S
Rivera
V M
VM
Crowe
P D
PD
Boehme
S A
SA
Zhang
J Z
JZ
D000409:Alanine / Q000276:immunology; D002478:Cells, Cultured; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology*; D018258:Herpesvirus 2, Human / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology*; D007371:Interferon-gamma / Q000032:analysis; D016753:Interleukin-10 / Q000032:analysis; D008239:Lysine / Q000276:immunology; D009103:Multiple Sclerosis / Q000276:immunology*; D004676:Myelin Basic Protein / Q000737:chemistry / Q000276:immunology*; D027383:Papillomaviridae / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D010649:Phenylalanine / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; C104448:myelin basic protein 83-99; D016753:Interleukin-10; D010649:Phenylalanine; D007371:Interferon-gamma; D008239:Lysine; D000409:Alanine