Microbial mimics supersize the pathogenic self-response

Microbial mimicry, the process in which a microbial antigen elicits an immune response and breaks tolerance to a structurally related self-antigen, has long been proposed as a mechanism in autoimmunity. In this issue of the JCI, Dolton et al. extend this paradigm by demonstrating that a naturally processed peptide from Klebsiella oxytoca acts as a superagonist for autoreactive T cells in type 1 diabetes (T1D). Reframing microbial mimics as superagonists that are thousands of times better at binding disease-associated autoreactive T cell receptors than self-peptides serves to narrow the search space for relevant sequences in the vast microbial proteome. Moreover, the identified superagonists have implications for the intervention and personalized monitoring of T1D that may carry over to other autoimmune diseases with microbial mimicry.