Physiological and pathogenic T cell autoreactivity converge in type 1 diabetes

Anne Eugster, Anna Lorenc, Martin Kotrulev, Yogesh Kamra, Manisha Goel, Katja Steinberg-Bains, Shereen Sabbah, Sevina Dietz, Ezio Bonifacio, Mark Peakman and Iria Gomez-Tourino ()
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Anne Eugster: Center for Regenerative Therapies Dresden
Anna Lorenc: Guy’s Hospital
Martin Kotrulev: University of Santiago de Compostela
Yogesh Kamra: Guy’s Hospital
Manisha Goel: Center for Regenerative Therapies Dresden
Katja Steinberg-Bains: Center for Regenerative Therapies Dresden
Shereen Sabbah: Guy’s Hospital
Sevina Dietz: Center for Regenerative Therapies Dresden
Ezio Bonifacio: Center for Regenerative Therapies Dresden
Mark Peakman: Guy’s Hospital
Iria Gomez-Tourino: Guy’s Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Autoimmune diseases result from autoantigen-mediated activation of adaptive immunity; intriguingly, autoantigen-specific T cells are also present in healthy donors. An assessment of dynamic changes of this autoreactive repertoire in both health and disease is thus warranted. Here we investigate the physiological versus pathogenic autoreactive processes in the context of Type 1 diabetes (T1D) and one of its landmark autoantigens, glutamic acid decarboxylase 65 (GAD65). Using single cell gene expression profiling and tandem T cell receptor (TCR) sequencing, we find that GAD65-specific true naïve cells are present in both health and disease, with GAD65-specific effector and memory responses showing similar ratios in healthy donors and patients. Deeper assessment of phenotype and TCR repertoire uncover differential features in GAD65-specific TCRs, including lower clonal sizes of healthy donor-derived clonotypes in patients. We thus propose a model whereby physiological autoimmunity against GAD65 is needed during early life, and that alterations of these physiological autoimmune processes in predisposed individuals trigger overt Type 1 diabetes.

Date: 2024
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DOI: 10.1038/s41467-024-53255-9

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