ATF4 drives regulatory T cell functional specification in homeostasis and obesity

Abstract

Regulatory T cells (T_regs) have diverse functional specification in homeostasis and disease. However, how liver T_regs function and are transcriptionally regulated in obesity is not well understood. Here, we identified that effector T_regs expressing activating transcription factor 4 (ATF4) were enriched in the livers of obese mice. ATF4 was critical for driving an effector T_reg transcriptional program, and ATF4-expressing T_regs promoted the development of obesity-induced liver fibrosis by enhancing transforming growth factor–β activation via integrin αvβ8. T_reg-specific deletion of Atf4 resulted in reduced liver T_regs and attenuation of obesity-induced liver abnormalities. Furthermore, ATF4 was required to promote the differentiation of nonlymphoid tissue T_reg precursors under steady state. These findings demonstrate that ATF4 is important for regulating T_reg functional specification in homeostasis and obesity.