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

Julie Noguerol, Karl Laviolette, Margot Zahm, Adeline Chaubet, Ambrine Sahal, Claire Détraves, Romain Torres, Clothilde Demont, Véronique Adoue, Carine Joffre, Florence Cammas, Joost PM Meerwijk and Olivier P. Joffre ()
Additional contact information
Julie Noguerol: Inserm U1291
Karl Laviolette: Inserm U1291
Margot Zahm: Inserm U1291
Adeline Chaubet: Inserm U1291
Ambrine Sahal: Inserm U1037
Claire Détraves: Inserm U1291
Romain Torres: Inserm U1291
Clothilde Demont: Inserm U1291
Véronique Adoue: Inserm U1291
Carine Joffre: Inserm U1037
Florence Cammas: Université Montpellier
Joost PM Meerwijk: Inserm U1291
Olivier P. Joffre: Inserm U1291

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-55848-4

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