Prevalent CD8+ T cell response against one peptide/MHC complex in autoimmune diabetes

B Anderson, BJ Park, J Verdaguer… - Proceedings of the …, 1999 - National Acad Sciences
B Anderson, BJ Park, J Verdaguer, A Amrani, P Santamaria
Proceedings of the National Academy of Sciences, 1999National Acad Sciences
Spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice is the result of a
CD4+ and CD8+ T cell-dependent autoimmune process directed against the pancreatic beta
cells. CD8+ T cells play a critical role in the initiation and progression of diabetes, but the
specificity and diversity of their antigenic repertoire remain unknown. Here, we define the
structure of a peptide mimotope that elicits the proliferation, cytokine secretion,
differentiation, and cytotoxicity of a diabetogenic H-2Kd-restricted CD8+ T cell specificity …
Spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice is the result of a CD4+ and CD8+ T cell-dependent autoimmune process directed against the pancreatic beta cells. CD8+ T cells play a critical role in the initiation and progression of diabetes, but the specificity and diversity of their antigenic repertoire remain unknown. Here, we define the structure of a peptide mimotope that elicits the proliferation, cytokine secretion, differentiation, and cytotoxicity of a diabetogenic H-2Kd-restricted CD8+ T cell specificity (NY8.3) that uses a T cell receptor α (TCRα) rearrangement frequently expressed by CD8+ T cells propagated from the earliest insulitic lesions of NOD mice (Vα17-Jα42 elements, often joined by the N-region sequence M-R-D/E). Stimulation of splenic CD8+ T cells from single-chain 8.3-TCRβ-transgenic NOD mice with this mimotope leads to preferential expansion of T cells bearing an endogenously derived TCRα chain identical to the one used by their islet-associated CD8+ T cells, which is also identical to the 8.3-TCRα sequence. Cytotoxicity assays using islet-derived CD8+ T cell clones from nontransgenic NOD mice as effectors and peptide-pulsed H-2Kd-transfected RMA-S cells as targets indicate that nearly half of the CD8+ T cells recruited to islets in NOD mice specifically recognize the same peptide/H-2Kd complex. This work demonstrates that beta cell-reactive CD8+ T cells mount a prevalent response against a single peptide/MHC complex and provides one peptide ligand for CD8+ T cells in autoimmune diabetes.
National Acad Sciences