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.