Oral Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

TCR affinity and tolerance mechanisms converge to shape T cell diabetogenic potential.Dario AA Vignali.Department of Immunology, St. Jude Children’s Research Hospital, Memphis TN 38138, USA. (#63)

Dario AA Vignali 1
  1. St. Jude Children's Research Hospital, Memphis, TN, United States

Autoreactive T cells infiltrating the target organ can possess a broad range of T cell receptor (TCR) affinities. However, it is still unclear how TCR affinity contributes to their diabetogenic potential and to what extent this is impacted by central and peripheral tolerance mechanisms. NOD retrogenic mice were generated expressing one of nine insulin B chain 9-23 (InsB.9-23)-specific TCRs with a broad range of physical and functional affinities. Surprisingly, TCR affinity did not correlate with pathogenicity, with both high and low affinity TCRs mediating autoimmune diabetes. A broad range of developmental and functional parameters are currently being evaluated to determine if correlations with diabetogenic potential exist. Interestingly, insulin-induced central tolerance and Foxp3+ regulatory T cell-mediated peripheral tolerance only limited the diabetogenic potential of higher affinity TCRs, as determined using Ins2–/– and Foxp3DTR NOD mice respectively. This may serve to ‘normalize’ the pathogenicity of high and low affinity clones, thereby broadening the autoreactive T cell repertoire.