Transcriptional programing of helper T cell metabolism by the IL-2-STAT5 axis

Activated lymphocytes adapt their metabolism to meet the energetic and biosynthetic demands imposed by rapid growth and proliferation. Common gamma chain (c𝛾) family cytokines are central to this process but the role of downstream STAT5 signaling, a cardinal feature of all members, remains loosely defined. Using genome-, transcriptome- and metabolome-wide analyses, we demonstrate that STAT5 is a master regulator of energy and amino acid metabolism in CD4+ ‘helper’ T cells. Mechanistically, we find that STAT5 localizes to a suite of enhancers and promoters for genes encoding essential, often rate-limiting enzymes and transporters, where it instructs transcription through p300 recruitment and epigenetic remodeling. We also find that STAT5 licenses the activity of other metabolic agents downstream of IL-2, namely the mTOR signaling pathway and the transcription factor, MYC, and present evidence for genome-wide cooperation between STAT5 and MYC in both normal and transformed T cells. Taken together, our data provide a molecular framework for transcriptional programing of T cell metabolism downstream of c𝛾 cytokines and emphasize the Jak-STAT pathway in powering cellular growth and proliferation. ChIP-seq and mRNA-seq analyses for STAT5 gain- and loss-of-funtion experiments in mouse CD4+ effector T cells