Type 1 diabetes (T1D) manifested with hyperglycemia is an autoimmune disease resulting from destruction of insulin-producing pancreatic β cells (1, 2). The nonobese diabetic (NOD) mouse is the preclinical model closest to T1D in man and has provided an invaluable understanding of basic immune pathogenesis, genetic and environmental risk factors, and immune-targeting strategies (3). However, investigators observed that histopathology in T1D patients differs significantly from that in NOD mice (4), and therapies developed with NOD mice are not easily directly translated into treating T1D patients (5). Due to ethical issues, much research on pathogenesis and therapies cannot be directly performed in T1D patients. Therefore, investigators have been attempting to develop humanized mouse models to better mimic pathogenesis and therapy in T1D patients. Humanized mice are generally defined as immunodeficient mice engrafted with human hematopoietic cells or tissues or mice that transgenically express human genes (6). In PNAS, Tan et al.(7) combined these two approaches and developed a new humanized model of T1D.

T1D pathogenesis in both NOD mice and humans is associated with a particular MHC haplotype (designated H2 in mice and HLA in humans), H2-IA g7 with H2-K d D b in NOD mice (8–10) and HLA-DQ8 or DR4 with HLA-A2 in humans (11, 12). In NOD mice, T1D is mediated by both autoreactive CD4+ and CD8+ T cells in collaboration with B cells and innate immune cells (3). Autoreactive CD4+ T cells in T1D recognize a variety of autoantigens presented by IA g7 MHCII, including insulin peptides (InsB9: 23) derived from proinsulin, GAD65 peptides, and hybrid insulin peptides (13, 14). InsB9: 23-reactive CD4+ T cells include type A and B subsets. The former recognize the higher-affinity InsB13-21 and are largely deleted during thymic negative selection, and the escaped ones are more likely to become suppressive regulatory CD4+ T cells (15). The latter subset recognize the lower-affinity InsB12-20 and easily escape from thymic negative selection and become the central players in the response against InsB: 9-23 during diabetogenesis (15). CD8+ T cells can recognize antigens presented by H2-K d MHC I such as islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)(16). It was reported that immune responses against proinsulin were necessary for IGRP-specific T cells to develop, indicating that response against IGRP is downstream of the response to proinsulin, and that the pathogenic proinsulin-specific immune response in NOD mice can subsequently spread to other antigens such as IGRP (17).