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

Regulatory T cell (Treg) insufficiency licenses the destruction of insulin-producing pancreatic ?-cells by autoreactive effector cells (Teffs), causing spontaneous autoimmune diabetes in NOD mice. We investigated contribution to T-cell receptor (TCR) repertoires naive regulatory (nTregs), activated/memory Tregs (amTregs), and CD4+ Teffs from prediabetic mice normal C57BL/6 (B6) amTreg Teff repertoire diversity was unexpectedly higher than that B6 This due presence highly expanded clonotypes amTregs were largely lost their counterparts. Interleukin-2 (IL-2) administration restored such clonotype expansions prevented development. In contrast, IL-2 only led few or no nTregs Teffs, respectively. Noteworthily, IL-2–expanded nTreg markedly enriched islet-antigen specific TCRs. Altogether, our results highlight link between a reduced expansion within activated Treg development an disease. They also indicate is amenable rejuvenation IL-2.