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Central tolerance induction by manipulation of thymic cell DNA and expression of GAD antigen by thymic epithelial cells

Science et RechercheLe Pouls AEEMUMComment
Central tolerance induction by manipulation of thymic cell DNA and expression of GAD antigen by thymic epithelial cells

Central tolerance induction by manipulation of thymic cell DNA and expression of GAD antigen by thymic epithelial cells

par Samaya Kanj, Michael Vladovsky, Anton Volniansky et Joe Zako

Faculté de médecine, Université de Montréal

The negative selection of immature T-cells produced by the bone marrow requires the presentation of tissue-specific antigens (ts-ags) by medullary thymic epithelial cells (mTECs) [1]. By this process, T-cells that recognize the ts-ags receive an apoptotic signal, leading to suppression of auto-immune reactions [2]. Such reaction occurs in type I diabetes when T-cells auto-react to GAD-ags [3]. The AIRE enzyme, expressed by mTECs and certain dendritic cells, plays a crucial role in the presentation of ts-ags, acting as a transcription factor that binds to the promoters of gene sequences for each ts-ag [4]. This project’s main objectives are induction of GAD presentation on major histocompatibility complexes in diabetic murine thymic cells so as to generate central tolerance to GAD antigen in CD4 and CD8 T-cells and cause antigen-specific Treg proliferation. To achieve this goal, thymic-cell-specific viral vectors loaded with CRISPR-Cas9 and GAD-coding DNA fragments will be delivered to the thymic epithelium. CRISPR Cas-9 will then insert the gene coding for a specific protein antigen into the genome of mTECs. The expected intracellular mechanism following this procedure would be demethylation of the newly added DNA strand by the AIRE enzyme during negative selection, enabling presentation of the GAD protein antigen by thymic cells to T-cells [5], which would induce tolerance to that specific antigen. Potential benefits of this research include incidence reduction of type 1 diabetes mellitus, an illness which affects 1/300 individuals in the US [6] ; extensively, other auto-immune diseases and tolerance to allografts could also be enhanced by induction of allograft-specific antigen presentation in the thymus.

Keywords : Thymus, Central tolerance, Thymic cells, mTECs, T-cells, CRISPR Cas-9, gene AIRE, Viral vectors, Autoimmune diseases, Allograft rejection.

Références

1 Twenty Years of AIRE. Perniola R (2018), Front. Immunol. [1]

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00098/full

2 - Idem [1]

3 - Antigen‐presenting cells expressing glutamate decarboxylase 67 were identified as epithelial cells in glutamate decarboxylase 67‐GFP knock‐in mouse thymus. Maemura, K., et al.. (2006),. Tissue Antigens, 67: 198-206. [2]

4 - Idem [1]

5 - Idem [1]

6 - Epidemiology of type 1 diabetes.Maahs DM, et al. Endocrinol Metab Clin North Am. 2010;39(3):481-497. doi:10.1016/j.ecl.2010.05.011

Image de couverture : https://en.wikipedia.org/wiki/T_cell#/media/File:Healthy_Human_T_Cell.jpg

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