Enhanced thymic selection of FoxP3 ⁺ regulatory T cells in the NOD mouse model of autoimmune diabetes

Abstract

FoxP3 ؉ CD4 ؉ regulatory T cells (Tregs) play a key role in the maintenance of peripheral self-tolerance, and it has been suggested that diabetes-susceptible nonobese diabetic (NOD) mice are defective in the generation and numbers of Tregs. We found thymic selection of Tregs to be under genetic control. Fetal thymic organ cultures on the NOD background required 3-to 10-fold more antigen than corresponding cultures on the B6 background for optimal induction of Tregs, but once the threshold for induction was reached the NOD background yielded close to 10-fold more Tregs. This increased selection of Tregs was also found in nontransgenic NOD mice in fetal through adult stages. This trait did not map to the MHC, idd3, or the chromosome 3 (Chr3) regions that control clonal deletion, but mainly to two regions on Chr1 and Chr11. Thus, NOD mice do not have a global defect in the generation or maintenance of Tregs; if anything, they show the opposite.genetic ͉ lineage commitment ͉ thymus

Increased thymic development of regulatory T cells in NOD mice is functionally dissociated from type I diabetes susceptibility

“…Trd1 fully explains the difference between NOD and B6 or B10 mice. The discrepancy between both studies may be explained by the phenotype analyzed, generation of Treg cells through fetal organ culture in the paper by Feuerer et al [11], and underscores the complexity of the trait studied.Trd1 does not contain the genes encoding antigen-presenting MHC class (I and) II molecules that are located telomeric to the Trd1 region. It therefore appears that these molecules are not involved in the quantitative difference of Foxp3 + CD4SP Treg-cell development in NOD vs. B6 mice.…”

“…Natural Treg cells are generated in the thymus where the processes of positive and negative selection shape their autospecific TCR repertoire [10]. Two groups have shown quantitative differences in Treg-cell development in NOD mice [11,12]. Feuerer et al [11] reported increased levels of Treg cells in NOD vs. B6.H-2 g7 thymi.…”

“…Two groups have shown quantitative differences in Treg-cell development in NOD mice [11,12]. Feuerer et al [11] reported increased levels of Treg cells in NOD vs. B6.H-2 g7 thymi. More recently, Yamanouchi et al [12] showed that the Idd9.1 diabetes susceptibility locus may quantitatively modulate thymic Treg-cell levels.…”

“…This region, which we named Trd1, is located on chromosome 17 centromeric to the H2-locus and is sufficient for the paradoxically and substantially increased number of Treg cells in the NOD thymus as compared with that in the B6 thymus. Importantly, whereas Trd1 and the diabetes-susceptibility locus Idd16 overlap, distinct genetic controls are involved, which strongly suggests that the increased Treg-cell development in NOD mice is functionally dissociated from their susceptibility to diabetes.Two other quantitative trait loci (QTL) implicated in the increased Treg-cell differentiation in NOD mice have previously been described, one on chromosome 1 and the other on chromosome 11 [11]. These QTL, responsible for less than 30% of the variance, were identified using (NODxB6-H2 g7 )F2 progeny.…”

CD4+CD25+Foxp3+ Regulatory T Cells Are Dispensable for Controlling CD8+ T Cell-Mediated Lung Inflammation

“…The fact that nTregs do not have to be the exclusive protective factor against autoimmune disease was previously demonstrated in autoimmunity-prone NOD mice, which surprisingly generate nTregs more effectively than do healthy mice (61).…”