How benign autoimmunity becomes detrimental in type 1 diabetes.

Central questions for organ-specific autoimmune diseases such as type 1 diabetes (T1D) are, What are the relevant self-antigens of the destructive processes and Why does the immune system become interested in them? In PNAS, Anderson et al. (1) provide more evidence that insulin and its precursors constitute a key antigen in T1D. Nakayama, Eisenbarth, and coworkers had previously demonstrated that autoimmune diabetes in the NOD mouse model does not develop without immune targeting of insulin (2, 3). Now, Nakayama and her team take advantage of T1D pancreas procurement programs to address insulin reactivity of CD8+ T cells found around the islets from seven patients with T1D. They sequenced the T cell receptors (TCRs) of islet CD8+ T cells and successfully expressed 142 clonotypes to examine their specificity against preproinsulin (PPI). This enormous undertaking found that 24 (17%) of the TCR clonotypes reacted against PPI peptides and a further three responded to peptides from defective ribosomal products of PPI messenger RNA (DRiP). Clonotypes responsive to PPI peptides were observed in all patients, although at varying frequencies, and peptides across the whole PPI molecule were targeted. CD8+ T cell clonotypes were present in at least two cells, suggesting that they had undergone local rounds of expansion. In islets from nondiabetic donors, reactivity to PPI or DRiP peptides was weaker and infrequently observed. The findings of Anderson et al. (1) are supported by several other studies. Peakman and coworkers isolated PPI-specific CD8+ T cell clones from the blood of patients with T1D (4), and Kent et al. isolated insulin-specific CD4+ T cells from pancreatic lymph nodes of patients (5). PPI-reactive CD8+ T cells were present in human islets during T1D pathogenesis (6) and also in the exocrine pancreas of healthy individuals, from where they appear to … [↵][1] 1To whom correspondence may be addressed. Email: matthias{at}lji.org. [1]: #xref-corresp-1-1