The nonobese diabetic (NOD) mouse, a model of spontaneous insulin- dependent diabetes mellitus (IDDM), fails to express surface MHC class II I- E(g7) molecules due a deletion in the Eα gene promoter. Eα-transgenic NOD mice express the EαEβ(g7) dimer and fail to develop either insulitis or IDDM. A number of hypotheses have been proposed to explain the mechanisms of protection, most of which require peptide binding to I-E(g7). To define the requirements for peptide binding to I-E(g7), we first identified an I-E(g7)- restricted T cell epitope corresponding to the sequence 4-13 of Mycobacterium tuberculosis 65-kDa heat shock protein (hsp). Single amino acid substitutions at individual positions revealed a motif for peptide binding to I-E(g7) characterized by two primary anchors at relative position (p) 1 and 4, and two secondary anchors at p6 and p9. This motif is present in eight of nine hsp peptides that bind to I-E(g7) with high affinity. The I-E(g7) binding motif displays a unique p4 anchor compared with the other known I-E motifs, and major differences are found between I-E(g7) and I-A(g7) binding motifs. Analysis of peptide binding to I-E(g7) and I-A(g7) molecules as well as proliferative responses of draining lymph node cells from hsp-primed NOD and Eα-transgenic NOD mice to overlapping hsp peptides revealed that the two MHC molecules bind different peptides. Of 80 hsp peptides tested, none bind with high affinity to both MHC molecules, arguing against some of the mechanisms hypothesized to explain protection from IDDM in Eα-transgenic NOD mice.
|Number of pages||11|
|Journal||Journal of Immunology|
|Publication status||Published - Jun 1 1999|
ASJC Scopus subject areas