Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human T cell clones.

Abstract

SllmmslmfImmunodominant T cell epitopes of myelin basic protein (MBP) may be target antigens for major histocompatibility complex class II-restricted, autoreactive T cells in multiple sclerosis (MS). Since susceptibility to MS is associated with the DR2 haplotype, the binding and presentation of the immunodominant MBP(84-102) peptide by DR2 antigens were examined. The immunodominant MBP(84-102) peptide was found to bind with high affinity to DRB1*1501 and DRB5*0101 molecules of the disease-associated DR2 haplotype. Overlapping but distinct peptide segments were critical for binding to these molecules; hydrophobic residues (Va1189 and Phe92) in the MBP(88-95) segment were critical for peptide binding to DRBl*1501 molecules, whereas hydrophobic and charged residues (Phe92, Lys93) in the MBP(89-101/102) sequence contributed to DRB5*0101 binding. The different registers for peptide binding made different peptide side chains available for interaction with the T cell receptor. Although the peptide was bound with high affinity by both DRB1 and DRB5 molecules, only DRB1 (DRB1*1501 and 1602) but not DRB5 molecules served as restriction elements for a panel of T cell clones generated from two MS patients suggesting that the complex of MBP(84-102) and DRB1 molecules is more immunogenic for MBP reactive T cells. The minimal MBP peptide epitope for several T cell clones and the residues important for binding to DRBl*1501 molecules and for T cell stimulation have been defined. Susceptibility to a variety of human autoimmune diseases is associated with alleles of MHC class I or class II genes. Examples of autoimmune diseases associated with MHC class II haplotypes include insulin dependent diabetes (DR3 and DR4 haplotypes), myasthenia gravis (DR3) and multiple sclerosis (DR2) (1-3). The major hypothesis is that these allelic gene products define the specificity of an immune attack against self-antigens by presentation of tissue specific selfpeptides to T cells.In the case of multiple sclerosis (MS)} this hypothesis implies that DR2 antigens (either DRB1*1501 or DRB5*0101 molecules encoded in the DR2 haplotype, or both) present self-peptides(s) from a myelin/oligodendrocyte antigen since the disease is restricted to the white matter of the central but not peripheral nervous system. Based on their encephalitogenicity in animal models (4-6), myelin basic pro-1 Abbreviations used in this paper: MBP, myelin basic protein; MNC, mononuclear cells; MS, multiple sclerosis; PLP, proteolipid protein.tein (MBP) and proteolipid protein (PLP) have long been viewed as the principal candidate antigens. The role of MBP and PLP reactive T ceils in the pathogenesis of MS has, however, been difficult to prove.In animal models, encephalomyelitis is mediated by T cells reactive with immunodominant determinants of MBP or PLP (4-6). In humans, two dominant T cell epitopes are located in the center and in the COOH-terminal portion of the molecule and MBP(143-168)] (7-10). These epitopes may be relevant to the pathogenesis of MS since both peptides ca...

Contribution of Individual Amino Acids Within MHC Molecule or Antigenic Peptide to TCR Ligand Potency

“…Overall, the PS-SCL data not only matched very well with the data obtained with single amino acid-modified peptides, but also with the known binding motifs for HLA-DR2a and HLA-DR2b (22,25,26). The responses of TCC TL3A6 to the PS-SCL demonstrate the importance of aromatic amino acids in pocket 1 (pocket 2), aliphatic residues in pocket 4 (pocket 5), and positively charged amino acids in position 8 (pocket 9) in the DR2a-binding motif.…”

Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling

“…As such, each class II allele binds and presents a distinct set of peptides based on the specific amino acid residues that comprise its peptide binding pockets. The peptide binding motifs for a number of class II alleles have been defined (2)(3)(4), but many remain unknown. Among these, DR1401 is of considerable interest because of its association with HLA driven HIV escape (5), protection from type I diabetes (6), and susceptibility to psoriasis vulgaris (7) in certain populations.…”

Polyspecificity of T cell and B cell receptor recognition

“…At the same time, the structural requirements for peptide binding to MHC molecules were elucidated, demonstrating that peptide-binding motifs were quite degenerate, in particular for MHC class II molecules [4][5][6][7]. Peptides with minimal sequence homology to the original peptide were identified by considering the requirements for both MHC binding and TCR recognition.…”