Why is it that normal individuals can harbour autoreactive T cells yet do not develop overt autoimmune disease? A recent report published in Nature Medicine provides a potential explanation for this conundrum and indicates that Toll-like receptor (TLR) ligation is required to cause destruction of pancreatic islet β-cells by autoreactive T cells in a mouse model of diabetes.

Zinkernagel and colleagues studied the RIP–GP mouse model of diabetes, in which a lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) transgene is expressed under the control of the rat insulin promoter (RIP). LCMV infection of these mice induces the clonal expansion of LCMV-GP-specific CD8+ T-cell populations and the development of hyperglycaemia. However, if RIP–GP mice were immunized with an LCMV-GP-derived peptide (gp33) together with CpG-containing oligodeoxynucleotides (to deliver co-stimulation), they did not develop diabetes, despite having large numbers of fully functional gp33-specific CD8+ T cells. The absence of disease was not a consequence of inefficient T-cell migration to the pancreas, as in mice that co-express LCMV-GP and the chemokine CXCL13 in the pancreas, gp33-specific CD8+ T cells infiltrated the pancreatic islets in response to immunization with gp33, yet these mice did not develop diabetes. Next, the authors observed that LCMV infection, but not gp33 immunization, increased the level of serum interferon-α (IFN-α), which upregulated MHC class I expression by β-cells. Pancreatic MHC class I expression could also be induced by administration of the TLR3 ligand polyI:C or the TLR7 ligand R848 to wild-type mice, and when administered to RIP–GP mice that were pre-immunized with gp33, hyperglycaemia developed. The ability of TLR ligands to induce disease was dependent on expression of the type I IFN receptor, indicating that expression of MHC class I in the pancreas in response to TLR-induced IFN-α production renders the pancreas susceptible to attack by autoreactive T cells.