Idd9.1 Locus Controls the Suppressive Activity of FoxP3(+)CD4(+)CD25(+) Regulatory T-Cells

OBJECTIVE: The ∼45-cM insulin-dependent diabetes 9 (Idd9) region on mouse chromosome 4 harbors several different type 1 diabetes–associated loci. Nonobese diabetic (NOD) mice congenic for the Idd9 region of C57BL/10 (B10) mice, carrying antidiabetogenic alleles in three different Idd9 subregions (Idd9.1, Idd9.2, and Idd9.3), are strongly resistant to type 1 diabetes. However, the mechanisms remain unclear. This study aimed to define mechanisms underlying the type 1 diabetes resistance afforded by B10 Idd9.1, Idd9.2, and/or Idd9.3. RESEARCH DESIGN AND METHODS: We used a reductionist approach that involves comparing the fate of a type 1 diabetes–relevant autoreactive CD8(+) T-cell population, specific for residues 206–214 of islet-specific glucose 6 phosphatase catalytic subunit–related protein (IGRP(206–214)), in noncongenic versus B10 Idd9–congenic (Idd9.1 + Idd9.2 + Idd9.3, Idd9.2 + Idd9.3, Idd9.1, Idd9.2, and Idd9.3) T-cell receptor (TCR)–transgenic (8.3) NOD mice. RESULTS: Most of the protective effect of Idd9 against 8.3-CD8(+) T-cell–enhanced type 1 diabetes was mediated by Idd9.1. Although Idd9.2 and Idd9.3 afforded some protection, the effects were small and did not enhance the greater protective effect of Idd9.1. B10 Idd9.1 afforded type 1 diabetes resistance without impairing the developmental biology or intrinsic diabetogenic potential of autoreactive CD8(+) T-cells. Studies in T- and B-cell–deficient 8.3-NOD.B10 Idd9.1 mice revealed that this antidiabetogenic effect was mediated by endogenous, nontransgenic T-cells in a B-cell–independent manner. Consistent with this, B10 Idd9.1 increased the suppressive function and antidiabetogenic activity of the FoxP3(+)CD4(+)CD25(+) T-cell subset in both TCR-transgenic and nontransgenic mice. CONCLUSIONS: A gene(s) within Idd9.1 regulates the development and function of FoxP3(+)CD4(+)CD25(+) regulatory T-cells and, in turn, the activation of CD8(+) effector T-cells in the pancreatic draining lymph nodes, without affecting their development or intrinsic diabetogenic potential.