Abstract
Improved mouse models for type 1 diabetes (T1D) therapy development are needed. T1D susceptibility is restored to normally resistant NOD.β2m(-/-) mice transgenically expressing human disease-associated HLA-A*02:01 or HLA-B*39:06 class I molecules in place of their murine counterparts. T1D is dependent on pathogenic CD8(+) T-cell responses mediated by these human class I variants. NOD.β2m(-/-)-A2.1 mice were previously used to identify β-cell autoantigens presented by this human class I variant to pathogenic CD8(+) T cells and for testing therapies to attenuate such effectors. However, NOD.β2m(-/-) mice also lack nonclassical MHC I family members, including FcRn, required for antigen presentation, and maintenance of serum IgG and albumin, precluding therapies dependent on these molecules. Hence, we used CRISPR/Cas9 to directly ablate the NOD H2-K(d) and H2-D(b) classical class I variants either individually or in tandem (cMHCI(-/-)). Ablation of the H2-A(g7) class II variant in the latter stock created NOD mice totally lacking in classical murine MHC expression (cMHCI/II(-/-)). NOD-cMHCI(-/-) mice retained nonclassical MHC I molecule expression and FcRn activity. Transgenic expression of HLA-A2 or -B39 restored pathogenic CD8(+) T-cell development and T1D susceptibility to NOD-cMHCI(-/-) mice. These next-generation HLA-humanized NOD models may provide improved platforms for T1D therapy development.