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Seattle - Jun 13, 2024

New Study in Nature Communications From Benaroya Research Institute Finds Islet Antigen Reactive TCR Alpha Chains are Shared Between Blood and Pancreas T Cells

Suggests IAR T cells May Be Useful Biomarkers for Impending Onset of Type 1 Diabetes

In an article published today in the journal Nature Communications, Benaroya Research Institute (BRI) scientists led by Peter Linsley, PhD and Karen Cerosaletti, PhD examined islet antigen reactive (IAR) T cells and compared T cell receptor (TCR) junction sequences in at-risk, type 1 diabetes (T1D) and healthy control patients. They found a significant fraction of IAR TCRs circulating in peripheral blood that share matching TCR alpha (TRA) chains with pancreatic infiltrating T cell (PIT) TCRs, and vice versa.

This finding is important for two reasons:

  • Direct investigation of pancreatic infiltrating T cells in T1D patients is not feasible, therefore much of the research into biomarkers of and potential therapies to prevent beta cell destruction is done on the IAR T cells circulating in the peripheral blood even though it has remained unclear whether these autoreactive cells in the blood represent autoimmunity in target organs.
  • IAR T cells are rare in the blood, which has made it difficult to determine a role for them in the progression of T1D and the pathogenesis of the disease in the pancreas. This supports the link between IAR T cells in blood, IAR T cells infiltrating the pancreas, and the progression of pancreatic destruction.
“We saw an expansion of TCR alpha chains in the circulating blood IAR T cells that matched those on T cells infiltrating the pancreas prior to and near the time of T1D diagnosis. This appearance of matching expanded alpha chains in the blood that closely precedes T1D diagnosis, suggests that circulating IAR T cells may be useful biomarkers of impending onset of T1D as well as potential targets for therapy to prevent the onset of disease.”
Peter Linsley, PhD

The research team’s results also suggest that PIT-matching TCRs have features of germline-like modes of antigen binding; they found that these TRA sequences are shorter and more hydrophobic with many cross-reactive TCRs. While cross-reactivity within TCRs expands potential interactions with foreign antigens, it also comes with greater potential for self-reactivity or autoimmunity. Little is known about TRA-centric antigen binding. However, this study suggests that TRA-centric binding may be a more widespread feature of IAR TCRs, and perhaps MHC class II-restricted TCRs in general.

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About Benaroya Research Institute

Benaroya Research Institute (BRI) is a world leader in human immune system research. BRI works to advance the science that will predict, prevent, reverse and cure immune system diseases like allergies, asthma, cancer, COVID-19 and autoimmune diseases. BRI accelerates discovery through laboratory breakthroughs in immunology that are then translated to clinical therapies. We believe that a breakthrough in one immune system disease can lead to progress against them all, and work tirelessly toward our vision of a healthy immune system for everyone. BRI is a world-renowned independent nonprofit research institute affiliated with Virginia Mason Franciscan Health and based in Seattle.

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