ATF4 drives regulatory T cell functional specification in homeostasis and obesity.

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