Structural features of autoreactive TCR that determine the degree of degeneracy in peptide recognition.
Structural aspects of human TCRs that allow the activation of autoreactive T cells by diverse microbial peptides were examined using two human myelin basic protein (MBP)-specific T cell clones. The TCR sequences of these clones differed only in the N region of TCR-alpha and -beta since the clones had the same Valpha-Jalpha and Vbeta-Jbeta rearrangements. The two clones had a similar fine specificity for the MBP peptide, except for the P5 position of the peptide (lysine). In the crystal structure of the HLA-DR2/MBP peptide complex, P5 lysine is a prominent, solvent-exposed residue in the center of the DR2/MBP peptide surface. Five microbial peptides with conservative or nonconservative changes at the P5 position (lysine to arginine, serine, or proline) activated one of these clones. In contrast, the other clone was activated only by three of these peptides which had a conservative lysine to arginine change at P5. The degree of specificity/degeneracy in recognition of the P5 side chain was the key difference between these TCRs since the Escherichia coli/Haemophilus influenzae peptide stimulated both clones when the P5 position was substituted from serine to arginine. These results demonstrate that the complementarity-determining region 3 loops contribute to the degree of degeneracy in peptide recognition by human MBP-specific TCRs.
Hausmann
S
S
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Martin
M
M
Gauthier
L
L
Wucherpfennig
K W
KW
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006825:Hybridomas; D051379:Mice; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*
D000942:Antigens, Bacterial; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C107908:myelin basic protein 85-99