Survivin promotes a glycolytic switch in CD4(+) T cells by suppressing the transcription of PFKFB3 in rheumatoid arthritis

In this study, we explore the role of nuclear survivin in maintaining the effector phenotype of IFNγ-producing T cells acting through the transcriptional control of glucose utilization. High expression of survivin in CD4(+)T cells was associated with IFNγ-dependent phenotype and anaerobic glycolysis. Transcriptome of CD4(+) cells and sequencing of survivin-bound chromatin showed that nuclear survivin had a genome-wide and motif-specific binding to regulatory regions of the genes controlling cell metabolism. Survivin coprecipitates with transcription factors IRF1 and SMAD3, which repressed the transcription of the metabolic check-point enzyme phosphofructokinase 2 gene PFKFB3 and promoted anaerobic glycolysis. Combining transcriptome analyses of CD4(+) cells and functional studies in glucose metabolism, we demonstrated that the inhibition of survivin reverted PFKFB3 production, inhibited glucose uptake, and reduces interferon effects in CD4(+) cells. These results present a survivin-dependent mechanism in coordinating the metabolic adaptation of CD4(+)T cells and propose an attractive strategy to counteract IFNγ-dependent inflammation in autoimmunity.