In the past decade, we participated in the increased use of HLA class II transgenic mice to delineate genetic control in autoimmune diseases. Our studies began with individual class II transgenes to determine permissiveness for experimental autoimmune thyroiditis (EAT), first in resistant strains and then in the absence of endogenous H2 class II molecules. Polymorphism for HLA-DRB1 was observed, as DR3, but not DR2 or DR4, molecules serve as a determinant for EAT induction with either mouse thyroglobulin (mTg) or human thyroglobulin (hTg). This delineation enabled identification of pathogenic Tg peptides, based on DR3-binding motifs. HLA-DQ polymorphism was also detectable; hTg induced moderate EAT in DQ8(+), but not DQ6(+), mice. Coexpressing permissive and nonpermissive alleles, DR3(+) mice showed reduced EAT severity in the presence of DQ8, but not DQ6, DR2, or DR4. Determining the regulatory T cell (Treg) influences showed that Treg depletion increased thyroiditis incidence and severity without altering the major histocompatibility complex-based hierarchy in susceptibility. This increase after Treg depletion can also be observed in NaI-induced thyroiditis in DR3(+) mice, a means to study a major environmental factor in thyroid autoimmunity. DR3(+) mice were also immunized with human thyroid peroxidase cDNA, resulting in thyroiditis and an antibody (Ab) profile resembling patient antibodies (Abs). Similar immunization with human TSH receptor cDNA resulted in thyroid-stimulating Abs and elevated T(4) levels with moderate thyroiditis in some animals, suggesting a potential Graves' disease model that due to thyroid lesions is more complete than other models. Recently, Treg manipulation in cancer immunotherapy trials has triggered various autoimmune disorders. Thus, DR3(+) mice are being used to monitor a known risk factor for autoimmune thyroid disease in attempts to enhance tumor immunity.