Heterochromatic gene silencing controls CD4+ T cell susceptibility to regulatory T cell-mediated suppression in a murine allograft model

Protective immune responses require close interactions between conventional (Tconv) and regulatory T cells (Treg). The extracellular mediators and signaling events that regulate the crosstalk between these CD4⁺ T cell subsets have been extensively characterized. However, how Tconv translate Treg-dependent suppressive signals at the chromatin level remains largely unknown. Here we show, using a murine bone marrow allograft model in which graft rejection is coordinated by CD4⁺ T cells and can be inhibited by Treg, that Treg-mediated T cell suppression involves Heterochromatin Protein 1 α (HP1α)-dependent gene silencing. Unexpectedly, our screen also reveals that T cells deficient for HP1γ or the methyltransferase SUV39H1 are better repressed by Treg than their wild-type counterparts. Mechanistically, our transcriptional and epigenetic profiling identifies HP1γ as a negative regulator of a gene network functionally associated with T-cell exhaustion, including those encoding the inhibitory receptors PD-1 and LAG-3. In conclusion, we identify HP1 variants as rheostats that finely tune the balance between tolerance and immunity. While HP1α converts immunosuppressive signals into heterochromatin-dependent gene silencing mechanisms, HP1γ adjusts Tconv sensitivity to inhibitory environmental signals.