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*
Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121; and
University of Toledo, College of Pharmacy, Toledo, OH 43606
CD4+ T cell responses to glutamic acid decarboxylase
(GAD65) spontaneously arise in nonobese diabetic (NOD) mice before the
onset of insulin-dependent diabetes mellitus (IDDM) and may be critical
to the pathogenic process. However, since both CD4+ and
CD8+ T cells are involved in autoimmune diabetes, we sought
to determine whether GAD65-specific CD8+ T cells were also
present in prediabetic NOD mice and contribute to IDDM. To refine the
analysis, putative Kd-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 spleen cells stimulated with GAD65
peptides 206–214 (p206) and 546–554 (p546) produced IFN-
and
showed Ag-specific CTL responses against targets pulsed with homologous
peptide. Conversely, several GAD peptides distal to the Th
determinants, and control Kd-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 p546-specific T cells transferred
insulitis to NOD.scid mice. Young NOD mice pretreated with p206 and
p546 showed reduced CTL responses to homologous peptides and a delay in
the onset of IDDM. Thus, MHC class I-restricted responses to GAD65 may
provide an inflammatory focus for the generation of islet-specific
pathogenesis and 
cell destruction. This report reveals a potential
therapeutic role for MHC class I-restricted peptides in treating
autoimmune disease and revisits the notion that the CD4- and
CD8-inducing determinants on some molecules may benefit from a proximal
relationship.
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