FIG. 6.

Lack of Foxp3 (scurfy mutation) significantly accelerates diabetes onset and increases penetrance in BDC12-4.1.RAG^KO mice. I-A^g7.BDC12-4.1.RAG^KO.Foxp3^wt (g7/g7 wt) TCR Tg male mice were crossed with I-A^b.Foxp3^{wt/mut(scurfy)} (C57BL/6 background) females (b/b wt/mut). The resulting back-cross generation 1 (BC1) I-A^g7/b.BDC12-4.1.RAG^+/−.Foxp3^wt/mut female and I-A^g7/b.BDC12-4.1.RAG^+/−.Foxp3^mut male mice were selected and intercrossed to generate all combinations. Of those, I-A^g7/g7.BDC12-4.1.RAG^KO.Foxp3^mut (g7/g7 mut) and I-A^g7/g7.BDC12-4.1.RAG^KO.Foxp3^wt (g7/g7 wt) male (A) or I-A^g7/g7.BDC12-4.1.RAG^KO.Foxp3^wt/mut (g7/g7 wt/mut) and I-A^g7/g7.BDC12-4.1.RAG^KO.Foxp3^mut/mut (g7/g7 mut/mut) female (B) offspring were monitored for diabetes development. In the absence of functional Foxp3, both male and female I-A^g7/g7.BDC12-4.1.RAG^KO mice diabetes develops faster, and disease is 100% penetrant (P < 0.0001). C: Diabetes development in BDC12-4.1.RAG^KO depends on both MHC I-A^g7/g7 (g7) and intact Foxp3. T1D development curve shown for the resulting BDC12-4.1.RAG^KO TCR Tg male mice from the aforementioned intercross. Whereas diabetes incidence in Foxp3 wt mice depends on the presence of the protective MHC allele I-A^b (0% diabetes in g7/b wt vs. 20% in g7/g7 wt), mice bearing the scurfy mutation (mut) develop fast and fully invasive diabetes irrespective their MHC genotype (100% diabetes in both g7/b mut and g7/g7 mut); females show similar results (data not shown).