TGF-β and Eomes control the homeostasis of CD8⁺ regulatory T cells

In addition to Foxp3⁺ CD4⁺ regulatory T cells (CD4⁺ T reg cells), Foxp3⁻ CD8⁺ regulatory T cells (CD8⁺ T reg cells) are critical to maintain immune tolerance. However, the molecular programs that specifically control CD8⁺ but not CD4⁺ T reg cells are largely unknown. Here, we demonstrate that simultaneous disruption of both TGF-β receptor and transcription factor Eomesodermin (Eomes) in T cells results in lethal autoimmunity due to a specific defect in CD8⁺ but not CD4⁺ T reg cells. Further, TGF-β signal maintains the regulatory identity, while Eomes controls the follicular location of CD8⁺ T reg cells. Both TGF-β signal and Eomes coordinate to promote the homeostasis of CD8⁺ T reg cells. Together, we have identified a unique molecular program designed for CD8⁺ T reg cells.