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

Abstract

Regulatory T cells (Treg) are immunosuppressive and negatively impact response to cancer immunotherapies. CREBbinding 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.

Prostaglandin I2 signaling licenses Treg suppressive function and prevents pathogenic reprogramming

“…However, our data would suggest the opposite, that PGI2 stimulation of IP results in β-catenin activation leading to its complexing with its transcriptional coactivator CBP resulting in enhanced Treg differentiation. As a whole, their overarching conclusion that PGI2 as well as CBP/p300 signaling is important for Treg differentiation supports our findings (69).…”

“…We were unable to confirm expression of PTGIS within Treg by Western blot or PCR (Supplemental Figure 14). Interestingly the authors were unable to find a direct effect of the PGI2 analog iloprost on Treg differentiation and concluded that CBP/p300 functions upstream of IP receptor stimulation and increased production of endogenous PGI2 mediates the effect of PTGIS on Treg differentiation via CBP/p300 (69). However, our data would suggest the opposite, that PGI2 stimulation of IP results in β-catenin activation leading to its complexing with its transcriptional coactivator CBP resulting in enhanced Treg differentiation.…”

“…Our study is unique in that the effects described are a result of PGI2 signaling within the Treg. Furthermore, a group of investigators found that Treg express PTGIS that is acetylated by CBP/p300 leading to increased production of PGI2 by Treg compared to naïve T cells (69). We were unable to confirm expression of PTGIS within Treg by Western blot or PCR (Supplemental Figure 14).…”

Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects

“…CBP/p300 are closely related acetyltransferases and transcriptional coactivators. CBP/p300 acetylates prostacyclin synthase, which regulates Tregs differentiation by altering pro-inflammatory cytokine secretion by T and B cells in follicular lymphoma [ 113 ]. The pro-autophagy protein AMBRA1 is also a key modulator of T cells, regulating the complex network that leads to human Tregs differentiation and maintenance.…”

The Route of Early T Cell Development: Crosstalk between Epigenetic and Transcription Factors

“…The reversible acetylation of lysine residues on histone tails is mediated by histone acetyltransferases (HATs) [ 156 ], including the CBP/p300 family of HATs [ 157 ]. The function of CBP/p300 has been elucidated in late T cell differentiation [ 158 , 159 ], but not much is known about their function during earlier stages. They acted as transcriptional coactivators, and deletion of either CBP or p300 resulted in a reduction of DP thymocytes, but the double knockout showed a more drastic decrease in the number of mature T cells [ 120 ].…”