Heterochromatin-dependent gene silencing pathways control CD4 T cell susceptibility to regulatory T cell-mediated suppression [RNAtreg]

ABSTRACT: The integrity of the organism depends on close and dynamic interactions between conventional and regulatory (Treg) T cells. The extracellular signals and signaling events that regulate this crosstalk have been extensively characterized. However, how conventional T cells translate Treg-dependent immunosuppressive signals at the chromatin level remains largely unknown. In differentiating CD4+ T helper (Th) cells, we and others previously reported that transcriptional specificity is largely controlled by heterochromatin-dependent gene silencing. We therefore hypothesized that Treg-mediated T cell suppression could also involve the repressive mark H3K9me3 and the histone-binding factor heterochromatin protein 1 (HP1). Using a bone marrow allograft model, in which graft rejection is coordinated by adoptively-transferred naive CD4+ T cells and can be inhibited by Treg, we show that Treg-dependent suppressive signals indeed mobilize HP1a to repress Th-cell effector genes. Unexpectedly, our screen also revealed that T cells deficient for HP1g or the lysine methyltransferase SUV39H1 are better tolerized than their wild-type counterparts. Mechanistically, our transcriptional and epigenetic profiling identified HP1g as a negative regulator of a network of genes functionally associated with T-cell anergy and exhaustion, including those encoding the transcription factor TOX and the inhibitory receptors PD-1, TIM-3 and LAG-3. In response to T cell receptor engagement, the expression of these immune checkpoints is deregulated in HP1g-deficient cells, thus promoting their better inhibition by Treg. Therefore, we demonstrate that H3K9me3-dependent epigenetic pathways critically regulate Th cell susceptibility to Treg-mediated suppression, and we identify HP1a and HP1g as new epigenetic players whose expression may be manipulated to restore protective immune responses or correct immunopathology, respectively.

ORGANISM(S): Mus musculus

PROVIDER: GSE246829 | GEO | 2024/11/25

REPOSITORIES: GEO