Amino acid variations at a single residue in an autoimmune peptide profoundly affect its properties: T-cell activation, major histocompatibility complex binding, and ability to block experimental allergic encephalomyelitis.
Myelin basic protein (MBP) or helper T cells reactive against MBP induce an autoimmune disease, experimental allergic encephalomyelitis, in B10.PL and PL/J inbred mice. In both strains, virtually the entire repertoire of MBP-specific T cells recognize an N-terminal peptide fragment in the context of the I-Au molecule encoded by the major histocompatibility complex (MHC) and utilize a very limited set of T-cell receptor genes. To delineate the nature of the trimolecular complex, consisting of the T-cell receptor, MBP-peptide fragment, and MHC molecule (I-Au), we have synthesized 13 variants of the 9-mer N-terminal immunodominant peptide differing at residue 4 and studied their immune recognition in vitro and in vivo. These substitutions have a striking range of effects on T-cell activation, ability to bind to the MHC molecule, and initiation of immune responses in vivo. An understanding of the autoimmune peptide/MHC/T-cell receptor interactions allowed us to design variant 9-mer peptides that have high affinity for an MHC molecule and are effective in blocking experimental allergic encephalomyelitis, possibly through two distinct mechanisms, peripheral T-cell tolerance and the inhibition of binding of the encephalitogenic peptide to the MHC molecules.
Division of Biology, California Institute of Technology, Pasadena 91125.
V
V
Kumar
J L
JL
Urban
S J
SJ
Horvath
L
L
Hood
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D004261:DNA Replication; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D007376:Interleukin-2 / Q000096:biosynthesis; D007700:Kinetics; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D008285:Major Histocompatibility Complex; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009154:Mutation; D004676:Myelin Basic Protein / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology*
D007376:Interleukin-2; D004676:Myelin Basic Protein