N-terminal flanking residues of a diabetes-associated GAD65 determinant are necessary for activation of antigen-specific T cells in diabetes-resistant mice.
A diabetes-associated peptide in the glutamic acid decarboxylase 65 (GAD65) molecule, p524-543, activates two distinct populations of T cells, which apparently play opposite roles in the development of diabetes in NOD mice. By comparing the fine specificity of these two T cell repertoires using a nested set of truncated peptides that cover the p524-543 region, we found, surprisingly, that all clones recognized the same core within this peptide, p530-539. The core itself was non-immunogenic, but the residues flanking this shared sequence played the crucial role in selecting T cells to activate. A peptide missing N-terminal flanking residues at position 528 and 529 was stimulatory in NOD but not in MHC-matched, NOD-resistant (NOR) mice, suggesting that a protective response in the resistant mice may require T cell recognition of one or more of the N-terminal flanking residues. T cell repertoire studies demonstrated selective clonal expansions within the BV4 TCR family that dominates the p524-543 response in NOD but not in NOR mice. These data suggest that processing or trimming events affecting T cell recognition of very few flanking residues of diabetes-associated determinants might be involved in the protective response in NOR mice.
Dai
Yang D
YD
Division of Immune Regulation, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121, USA.
Jensen
Kent P
KP
Marrero
Idania
I
Li
Ningli
N
Quinn
Anthony
A
Sercarz
Eli E
EE
D000818:Animals; D000941:Antigens / Q000276:immunology*; D021901:DNA, Intergenic / Q000235:genetics*; D003920:Diabetes Mellitus / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007114:Immunization; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000941:Antigens; D021901:DNA, Intergenic; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2