Type-1 immunity drives early lethality in scurfy mice

Foxp3(+) regulatory T (Treg) cells modulate the functions of multiple immune cell types, and loss of Treg cells causes lethal, CD4(+) T-cell-dependent multiorgan autoimmune disease in both mice and humans. However, how different effector T-cell subets contribute to the severe autoimmunity observed in the absence of Treg cells remains controversial. We found that although expanded populations of Th1, Th2, and Th17 cells can be detected in scurfy (sf) mice, Th1 cells predominate. Moreover, using a genetic approach, we found that sf mice with deficiencies in type-1 immunity (sf × Ifngr1(-/-), sf × Tbx21(-/-), and sf × Ifngr1(-/-)/Tbx21(-/-)) have an extended lifespan that is associated with altered cytokine production and attenuated cutaneous and hepatic inflammation. By contrast, sf mice deficient in type-2 immune responses (sf × Stat6(-/-)) display a significantly reduced lifespan with increased hepatic inflammation, but decreased dermatitis. These data indicate that Th1 cells and their associated cytokines drive early immunopathology in Foxp3-deficient sf mice, highlighting the essential role of Treg cells in restraining Th1-cell-mediated autoimmunity.