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Regulating the regulatory cells: Regulatory T cells (Tregs) are antigen-specific immunosuppressive cells that help prevent undesired immune responses. Chimeric antigen receptors (CARs) are engineered T cell receptors that allow direct recognition of a target antigen without requiring antigen presentation. CARs, most often, have been used with conventional T cells, directing them to attack cancer cells, for example. CAR Tregs have also been developed for treating autoimmune disorders or transplant rejection, but their biology is not as well understood. Dawson et al. addressed this knowledge gap by systematically studying and optimizing CAR signaling domains in Tregs and then applying them to a mouse model of graft-versus-host disease. Antigen-specific regulatory T cells (Tregs) engineered with chimeric antigen receptors (CARs) are a potent immunosuppressive cellular therapy in multiple disease models and could overcome shortcomings of polyclonal Treg therapy. CAR therapy was initially developed with conventional T cells, which have different signaling requirements than do Tregs. To date, most of the CAR Treg studies used second-generation CARs, encoding a CD28 or 4-1BB co-receptor signaling domain and CD3ζ, but it was not known if this CAR design was optimal for Tregs. Using a human leukocyte antigen–A2–specific CAR platform and human Tregs, we compared 10 CARs with different co-receptor signaling domains and systematically tested their function and CAR-stimulated gene expression profile. Tregs expressing a CAR encoding CD28wt were markedly superior to all other CARs tested in an in vivo model of graft-versus-host disease. In vitro assays revealed stable expression of Helios and an ability to suppress CD80 expression on dendritic cells as key in vitro predictors of in vivo function. This comprehensive study of CAR signaling domain variants in Tregs can be leveraged to optimize CAR design for use in antigen-specific Treg therapy. [ABSTRACT FROM AUTHOR]