Tuesday, February 6, 2018

T1D target epitope from zinc transporter 8 (ZnT8) cross-reacts with commensal bacteria

Type 1 diabetes (T1D) is considered autoimmune disease. Of course, in humans, we don't have a direct evidence that islet-specific auto-reactive T cells and auto-antibodies found in peripheral blood from T1D patients are indeed responsible for tissue damage. Such evidence would require T/B cell and Ab depletion experiment that is not feasible. Autoimmune nature of T1D is basically extrapolated from mouse studies or in vitro antigen binding assays.   

Several islet antigens are known to represent targets in T1D, such as preproinsulin (PPI), glutamic acid decarboxylase (GAD), insulinoma-associated protein-2 (IA-2), islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) and more recently described zinc transporter 8 (its peptide ZnT8186–194).

New study in Science Immunology found that ZnT8186–194-specific CD8 T cells are largely similarly present in both T1D patients and healthy controls and that ZnT8186–194-specific CD8 T cells could recognize (cross-react) peptide derived from gut commensal microbe Bacteroides stercoris.

Staining with ZnT8186–194-specific HLA class I multimers (MMr) and other functional antigen-specific assays found that T1D and healthy controls harbored largely similar number and functional ZnT8186–194-specific CD8 T cells.

Interestingly, ZnT8186–194-specific CD8 T cells could be double stained with HLA class I multimer + peptide derived from B. stercoris, a commensal bacterial species found in gut flora. It is not the first time such cross-reactivity has been observed between islet-specific CD8 T cells and commensal bacteria. Previously, at least two bacterial species have been identified to cross-react with IGRP-specific CD8 T cells.

In summary, this study indicates that deletion of auto-reactive CD8 T cells in the thymus is not sufficient to prevent autoimmunity and that regulatory mechanisms operating in the periphery is necessary to prevent initiation of auto-reactive attack by circulating ZnT8186–194-specific CD8 T cells (probably Tregs the authors had in mind). Cross-reactive peptide derived from B. stercoris could play role in priming of ZnT8186–194-specific CD8 T cells in absence of regulatory circuit. But how and why such antigen-specific tolerance breakdown happens in one and not in another is not clear at this stage.

posted by David Usharauli

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