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

Yamanouchi, Jun; Puertas, Maria-Carmen; Verdaguer, Joan; Lyons, Paul A.; Rainbow, Daniel B.; Chamberlain, Giselle; Hunter, Kara M.; Peterson, Laurence B.; Wicker, Linda S.; Santamaria, Pere
January 2010
Diabetes;Jan2010, Vol. 59 Issue 1, p272
Academic Journal
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 (IGRP206-214), 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. Diabetes 59:272-281,2010


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