Diabetogenic CD8 T cells recognize beta-cell antigens with high adaptability

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B775
Abstract ID: 7962

Presenting Author:
Baoyu Liu , Assistant Professor at Univ. of Utah

Abstract:

The hallmark of type I diabetes (T1D) is the autoimmune destruction of insulin-producing beta-cells in the pancreatic islets. CD8 T cells are required in this “mistaken” immune response driven by their specific recognition of beta-cell self-antigens. However, self-antigen recognition by diabetogenic CD8 T cells remains poorly understood. In this study, we have characterized islet-antigen recognition in the context of CD8 T cell thymic selection and peripheral activation. We used two-dimensional (2D) force-based assays to measure affinity and bond lifetime of the TCR:pMHC:CD8 interaction on live T cells. We found that CD8 T cells form weak bonds with beta-cell antigens during thymocyte selection but can greatly increase bond strength upon activation where CD8 plays a central role. Such adaptive self-recognition occurs at the single TCR clonal level. In contrast, the same parameters did not change for foreign antigen recognition. These data support our working hypothesis that in autoimmune diabetes, CD8 fundamentally alters self-antigen recognition through modulation of TCR binding kinetics, thereby endowing CD8 T cells with the ability to avoid thymic negative selection but allow heightened self-reactivity in the periphery that can overcome self-tolerance to mediate beta-cell destruction and precipitate disease. Elucidation of the underlying molecular mechanisms will inform novel therapeutic strategies to specifically target autoimmune CD8 T cells.