Heterochromatic gene silencing controls CD4+ T cell susceptibility to regulatory T cell-mediated suppression in a murine allograft model
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...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55848-4 |
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| author | Julie Noguerol Karl Laviolette Margot Zahm Adeline Chaubet Ambrine Sahal Claire Détraves Romain Torres Clothilde Demont Véronique Adoue Carine Joffre Florence Cammas Joost PM van Meerwijk Olivier P. Joffre |
| author_facet | Julie Noguerol Karl Laviolette Margot Zahm Adeline Chaubet Ambrine Sahal Claire Détraves Romain Torres Clothilde Demont Véronique Adoue Carine Joffre Florence Cammas Joost PM van Meerwijk Olivier P. Joffre |
| author_sort | Julie Noguerol |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c265ef2fada948c6b3a70f6841e829e8 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-c265ef2fada948c6b3a70f6841e829e82025-01-12T12:30:08ZengNature PortfolioNature Communications2041-17232025-01-0116111810.1038/s41467-025-55848-4Heterochromatic gene silencing controls CD4+ T cell susceptibility to regulatory T cell-mediated suppression in a murine allograft modelJulie Noguerol0Karl Laviolette1Margot Zahm2Adeline Chaubet3Ambrine Sahal4Claire Détraves5Romain Torres6Clothilde Demont7Véronique Adoue8Carine Joffre9Florence Cammas10Joost PM van Meerwijk11Olivier P. Joffre12Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291Centre de Recherche en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291Centre de Recherche en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université MontpellierInfinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291Infinity, Toulouse Institute for Infectious and Inflammatory Diseases, University of Toulouse, Inserm U1291Abstract 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.https://doi.org/10.1038/s41467-025-55848-4 |
| spellingShingle | Julie Noguerol Karl Laviolette Margot Zahm Adeline Chaubet Ambrine Sahal Claire Détraves Romain Torres Clothilde Demont Véronique Adoue Carine Joffre Florence Cammas Joost PM van Meerwijk Olivier P. Joffre Heterochromatic gene silencing controls CD4+ T cell susceptibility to regulatory T cell-mediated suppression in a murine allograft model Nature Communications |
| title | Heterochromatic gene silencing controls CD4+ T cell susceptibility to regulatory T cell-mediated suppression in a murine allograft model |
| title_full | Heterochromatic gene silencing controls CD4+ T cell susceptibility to regulatory T cell-mediated suppression in a murine allograft model |
| title_fullStr | Heterochromatic gene silencing controls CD4+ T cell susceptibility to regulatory T cell-mediated suppression in a murine allograft model |
| title_full_unstemmed | Heterochromatic gene silencing controls CD4+ T cell susceptibility to regulatory T cell-mediated suppression in a murine allograft model |
| title_short | Heterochromatic gene silencing controls CD4+ T cell susceptibility to regulatory T cell-mediated suppression in a murine allograft model |
| title_sort | heterochromatic gene silencing controls cd4 t cell susceptibility to regulatory t cell mediated suppression in a murine allograft model |
| url | https://doi.org/10.1038/s41467-025-55848-4 |
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