Abstract
Murine experimental allergic encephalomyelitis (EAE) is a useful model for the demyelinating, autoimmune disease multiple sclerosis. In the EAE system, the immunodominant N-terminal epitope of myelin basic protein (MBP) is an unusually short, weakly binding peptide antigen which elicits highly biased TCR chain usage. In the 2.2 Å crystal structure of I-Au/MBP1-11 complex, only MBP residues 1-7 are bound toward one end of the peptide binding cleft. The fourth residue of MBP1-11 is located in an incompatible p6 pocket of I-Au, thus explaining the short half-life of I-Au complexed with Ac1-11. MBP peptides extended at the C terminus of Ac1-11 result in dramatic affinity increases, likely attributed to register shifting to a higher affinity cryptic epitope, which could potentially mask the presentation of the immunodominant MBP1-11 peptide during thymic education.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 83-94 |
| Number of pages | 12 |
| Journal | Immunity |
| Volume | 17 |
| Issue number | 1 |
| DOIs | |
| State | Published - 2002 |
Funding
We thank H. McDevitt, L. Steinman, and M. Davis for comments on the manuscript, I. Wilson for discussion of unpublished results, J. Ho for technical assistance, and the staff of the Stanford Synchrotron Radiation Laboratory for beamline resources and support. We are grateful to Mei Han for carrying out functional assays with soluble pMHC complexes and Mihail Firan for assistance with expression vector construction. K.C.G. is funded by NIH RO1 AI48540, the Multiple Sclerosis Society, and the Rita Allen Foundation. X.H. is supported by the American Heart Association, the California Cancer Research Program, and a Stanford Dean's Fellowship. E.S.W. is funded by grants RO1 AI/NS 42949 (NIH), RG-2411 (NMSS), and the Yellow Rose Foundation. J.S. and A.S. acknowledge NIH-NIAID contract N01-AI-95362.
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Infectious Diseases