MHC class I-restricted determinants on the glutamic acid decarboxylase 65 molecule induce spontaneous CTL activity

CD4(+) T cell responses to glutamic acid decarboxylase (GAD65) spontaneousl y arise in nonobese diabetic (NOD) mice before the onset of insulin-depende nt diabetes mellitus (IDDM) and may be critical to the pathogenic process. However, since both CD4(+) and CD8(+) T cells are involved in autoimmune di abetes, we sought to determine whether GAD65-specific CD8(+) T cells were a lso present in prediabetic NOD mice and contribute to IDDM. To refine the a nalysis, putative K-d-binding determinants that were proximal to previously described dominant Th determinants (206-220 and 524-543) were examined for their ability to elicit cytolytic activity in young NOD mice. Naive NOD sp leen cells stimulated with GAD65 peptides 206-214 (p206) and 546-554 (p546) produced IFN-gamma and showed Ag-specific CTL responses against targets pu lsed with homologous peptide. Conversely, several GAD peptides distal to th e Th determinants, and control K-d-binding peptides did not induce similar responses. Spontaneous CTL responses to p206 and p546 were mediated by CD8( +) T cells that are capable of lysing GAD65-expressing target cells, and p5 46-specific T cells transferred insulitis to NOD.scid mice. Young NOD mice pretreated with p206 and p546 showed reduced CTL responses to homologous pe ptides and a delay in the onset of IDDM. Thus, MHC class I-restricted respo nses to GAD65 may provide an inflammatory focus for the generation of islet -specific pathogenesis and beta cell destruction. This report reveals a pot ential therapeutic role for MHC class I-restricted peptides in treating aut oimmune disease and revisits the notion that the CD4- and CD8-inducing dete rminants on some molecules may benefit from a proximal relationship.