CBP/p300 Drives the Differentiation of Regulatory T Cells through Transcriptional and Non-Transcriptional Mechanisms

Cancer Res. 2019 Aug 1;79(15):3916-3927. doi: 10.1158/0008-5472.CAN-18-3622. Epub 2019 Jun 10.


Regulatory T cells (Treg) are immunosuppressive and negatively impact response to cancer immunotherapies. CREB-binding protein (CBP) and p300 are closely related acetyltransferases and transcriptional coactivators. Here, we evaluate the mechanisms by which CBP/p300 regulate Treg differentiation and the consequences of CBP/p300 loss-of-function mutations in follicular lymphoma. Transcriptional and epigenetic profiling identified a cascade of transcription factors essential for Treg differentiation. Mass spectrometry analysis showed that CBP/p300 acetylates prostacyclin synthase, which regulates Treg differentiation by altering proinflammatory cytokine secretion by T and B cells. Reduced Treg presence in tissues harboring CBP/p300 loss-of-function mutations was observed in follicular lymphoma. Our findings provide novel insights into the regulation of Treg differentiation by CBP/p300, with potential clinical implications on alteration of the immune landscape. SIGNIFICANCE: This study provides insights into the dynamic role of CBP/p300 in the differentiation of Tregs, with potential clinical implications in the alteration of the immune landscape in follicular lymphoma.

MeSH terms

  • Acetylation
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CREB-Binding Protein / antagonists & inhibitors
  • CREB-Binding Protein / genetics
  • CREB-Binding Protein / immunology*
  • Cell Differentiation / physiology
  • Down-Regulation
  • E1A-Associated p300 Protein / antagonists & inhibitors
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / immunology*
  • Histones / metabolism
  • Humans
  • Lymphoma, Follicular / genetics
  • Lymphoma, Follicular / immunology*
  • Lymphoma, Follicular / metabolism
  • Lymphoma, Follicular / pathology
  • Mutation
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Transcription, Genetic
  • Transcriptome


  • GNE-781
  • Histones
  • Pyrazoles
  • Pyridines
  • CREB-Binding Protein
  • CREBBP protein, human
  • E1A-Associated p300 Protein
  • EP300 protein, human