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Impaired Activated/Memory Regulatory T Cell Clonal Expansion Instigates Diabetes in NOD Mice

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posted on 22.01.2021, 00:07 by Vanessa Mhanna, Gwladys Fourcade, Pierre Barennes, Valentin Quiniou, Hang P. Pham, Paul-Gydeon Ritvo, Faustine Brimaud, Bruno Gouritin, Guillaume Churlaud, Adrien Six, Encarnita Mariotti-Ferrandiz, David Klatzmann
Regulatory T cell (Treg) insufficiency licenses the destruction of insulin-producing pancreatic b cells by auto-reactive effector T cells (Teffs), causing spontaneous autoimmune diabetes in non‑obese diabetic (NOD) mice. We investigated the contribution to diabetes of the TCR repertoires of naive regulatory T cells (nTregs), activated/memory Tregs (amTregs), and CD4+ Teffs from prediabetic NOD mice and normal C57BL/6 (B6) mice. NOD mice amTreg and Teff repertoire diversity was unexpectedly higher than that of B6 mice. This was due to the presence of highly expanded clonotypes in B6 amTregs and Teffs that were largely lost in their NOD counterparts. IL-2 administration to NOD mice restored such amTreg clonotype expansions and prevented diabetes development. In contrast, IL-2 administration only led to few or no clonotype expansions in nTregs and Teffs, respectively. Noteworthily, IL-2 expanded amTreg and nTreg clonotypes were markedly enriched in islet-antigen specific TCRs. Altogether, our results highlight the link between a reduced clonotype expansion within the activated Treg repertoire and the development of an autoimmune disease. They also indicate that the repertoire of amTregs is amenable to rejuvenation by IL-2.

Funding

This work was funded by the TRiPoD ERC-Advanced EU (No. 322856) and RHU iMAP (ANR-16-RHUS-0001) grants to DK, with additional support from the Sorbonne Université, INSERM and AP-HP. ILTOO pharma supported HPP.

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