Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection

Abstract

In response to infection, pathogen-specific CD8 T cells differentiate into functionally diverse effector and memory T cell populations critical for resolving disease and providing durable immunity. Through small-molecule inhibition, RNAi studies, and induced genetic deletion, we reveal an essential role for the chromatin modifier and BET family member BRD4 in supporting the differentiation and maintenance of terminally fated effector CD8 T cells during infection. BRD4 bound diverse regulatory regions critical to effector T cell differentiation and controlled transcriptional activity of terminal effector–specific super-enhancers in vivo. Consequentially, induced deletion of Brd4 or small molecule–mediated BET inhibition impaired maintenance of a terminal effector T cell phenotype. BRD4 was also required for terminal differentiation of CD8 T cells in the tumor microenvironment in murine models, which we show has implications for immunotherapies. Taken together, these data reveal an unappreciated requirement for BRD4 in coordinating activity of cis regulatory elements to control CD8 T cell fate and lineage stability.

Brd4 Regulates the Homeostasis of CD8+ T-Lymphocytes and Their Proliferation in Response to Antigen Stimulation

“…8). Importantly, in consistent with our finding, a recent study also supports the importance of Brd4 in CD8 + T cells differentiation, in which Brd4 bound diverse regulatory regions of effector-related genes to enforce terminal differentiation of CD8 + T cells in the setting of viral infection and tumorigenesis (46). However, our study proved the indispensable role of Brd4 in CD8 + T cells from different perspectives: (1) Brd4 regulates naïve CD8 + T cells homeostasis by controlling naïve CD8 + T cells survival and trafficking, as Brd4 deficiency results in remarkable loss of CD8 + T cells and altered CD8 + T cells population in the steady-state; (2) Brd4 establishes a novel link between epigenetic regulation and immune metabolism by controlling GLUT1 expression; (3) Brd4 inhibition raises the concern/potential risk of immunosuppressive effect in viral infection therapy, such as HIV-1 latency, based on the critical role of Brd4 in promoting the clonal expansion and effector differentiation of CD8 + T cells in vivo.…”

Inhibiting BRD4 to generate BETter T cell memory

“…Various transcription factors (TFs) such as T-bet (Joshi et al, 2007) and Eomes (Banerjee et al, 2010) are important for the function and cell fates of TE and MP cells, respectively. Work by Milner et al (2021) in this issue of JEM sheds further light on the pathways regulating TE and MP cell formation by revealing a critical role for the bromodomain-containing protein BRD4 in the formation of TE CD8 T cells.…”

“…The work published by Milner et al (2021) in this issue of JEM sheds light on the role of BRD4 in the function and differentiation of CD8 T cells. Yet, as is always the case in science, every answer also raises more questions.…”

“…Overlap between BRD4 binding and H3K27ac modification was seen in genes important for TE cell function, including the transcription factor Id2 and the chemokine receptor Cx3cr1 . Milner et al further characterized the epigenetic functions of BRD4 by analyzing ChIP-seq data collected from TE cells to investigate the binding of BRD4 to super-enhancers, genomic regions containing several enhancers in close proximity ( Milner et al, 2021 ; Lovén et al, 2013 ). Intriguingly, ChIP-seq data demonstrated that BRD4 binds to 549 of 554 super-enhancers in TE cells, mirroring the known binding of BRD4 to super-enhancers in other cell types ( Dey et al, 2019 ; Lovén et al, 2013 ).…”

“…It would therefore be valuable to explore the link between fatty acid oxidation, histone acetylation, and BRD4 binding in the setting of cancer. In short, work by Milner et al (2021) in this issue of JEM has unveiled possibilities for new modes of therapeutic immunomodulation in acute and chronic infections, cancer, and autoimmunity.…”