The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue–resident regulatory T cells

Ajithkumar Vasanthakumar, Kazuyo Moro, Annie Xin, Yang Liao, Renee Gloury, Shimpei Kawamoto, Sidonia Fagarasan, Lisa A Mielke, Shoukat Afshar-Sterle, Seth L Masters, Susumu Nakae, Hirohisa Saito, John M Wentworth, Peng Li, Wei Liao, Warren J Leonard, Gordon K Smyth, Wei Shi, Stephen L Nutt, Shigeo Koyasu, Axel Kallies

Foxp3(+) regulatory T (Treg) cells in visceral adipose tissue (VAT-Treg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-γ; however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-Treg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-Treg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-Treg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-Treg cell homeostasis.