A small number of residues in the class II molecule I-Au confer the ability to bind the myelin basic protein peptide Ac1-11

A small number of residues in the class II molecule I-A^u confer the ability to bind the myelin basic protein peptide Ac1-11

Departments of ^*Microbiology and Immunology, and ^¶Medicine, Stanford University Medical Center, Stanford, CA 94305

Contributed by Hugh O. McDevitt

Abstract

The N-terminal peptide Ac1-11 of myelin basic protein induces experimental autoimmune encephalomyelitis in H-2^u and (H-2^u × H-2^s) mice but does not in H-2^s mice. Ac1-11 binds weakly to the class II major histocompatibility complex (MHC) molecule I-A^u but not at all to I-A^s. We have studied the interaction of Ac1-11 and I-A^u as a model system for therapeutic intervention in the autoimmune response seen in experimental autoimmune encephalomyelitis. Two polymorphic residues that differ between I-A^u and I-A^s, Y26β and T28β, and one conserved residue, E74β, confer specific binding of Ac1-11 to I-A^u. A fourth residue, R70β in I-A^u, affects both peptide binding and T cell recognition. These results are consistent with a model that places arginine at position five of Ac1-11 in pockets 4 and 7 of the MHC groove, which is formed in part by residues 26, 28, 70, and 74 of Aβ^u and places lysine at position four of Ac1-11, previously shown to be a major MHC contact, in hydrophobic pocket 6. The data indicate that the primary region of I-A^u that confers specific binding of Ac1-11 lies in the center of the peptide binding groove rather than in the region that contacts the N terminus of the peptide, as has been shown for HLA DR and the homologous I-E molecules.

Footnotes

↵ † Present address: Human Genetics Group, Department of Clinical Sciences, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.
↵ ‡ Present address: Committee on Immunology, University of Chicago, Chicago, IL 60637.
↵ § Present address: Cellular Immunology Laboratory and Institut National de la Santé et de la Recherche Médicale U134, Hopital Pitié-Salpêtrière, 75013 Paris, France.
↵ ‖ To whom reprint requests should be addressed at: Fairchild Building D345, Department of Microbiology and Immunology, Stanford University Medical Center, Stanford, CA 94305. e-mail: hughmcd{at}leland.stanford.edu.
ABBREVIATIONS:

EAE,

experimental autoimmune encephalomyelitis;

MBP,

myelin basic protein;

HVR,

hypervariable region;

MHC,

major histocompatibility complex;

TCR,

T cell antigen receptor