RESUMEN
Progenitor-like CD8+ T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing the single-cell transcriptomes and epigenetic profiles of CD8+ T cells responding to acute and chronic viral infections, we found that progenitor-like CD8+ T cells became distinct from memory precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the persistence of antiviral CD8+ T cells and was required for the programming of progenitor-like CD8+ T cells. Thus, long-term CD8+ T cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Regulación de la Expresión Génica , Proteínas de Homeodominio/genética , Infecciones/etiología , Análisis de la Célula Individual , Animales , Biomarcadores , Inmunoprecipitación de Cromatina , Epigénesis Genética , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas de Homeodominio/metabolismo , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Memoria Inmunológica , Infecciones/metabolismo , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Factores de Tiempo , TranscriptomaRESUMEN
T cell senescence and exhaustion are major barriers to successful cancer immunotherapy. Here we show that miR-155 increases CD8+ T cell antitumor function by restraining T cell senescence and functional exhaustion through epigenetic silencing of drivers of terminal differentiation. miR-155 enhances Polycomb repressor complex 2 (PRC2) activity indirectly by promoting the expression of the PRC2-associated factor Phf19 through downregulation of the Akt inhibitor, Ship1. Phf19 orchestrates a transcriptional program extensively shared with miR-155 to restrain T cell senescence and sustain CD8+ T cell antitumor responses. These effects rely on Phf19 histone-binding capacity, which is critical for the recruitment of PRC2 to the target chromatin. These findings establish the miR-155-Phf19-PRC2 as a pivotal axis regulating CD8+ T cell differentiation, thereby paving new ways for potentiating cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Melanoma Experimental/inmunología , MicroARNs/metabolismo , Neoplasias Cutáneas/inmunología , Factores de Transcripción/metabolismo , Traslado Adoptivo/métodos , Animales , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/trasplante , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Senescencia Celular/genética , Senescencia Celular/inmunología , Epigénesis Genética/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Melanoma Experimental/genética , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/genética , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatasas/metabolismo , Complejo Represivo Polycomb 2/inmunología , Complejo Represivo Polycomb 2/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/terapia , Factores de Transcripción/genética , Factores de Transcripción/inmunologíaRESUMEN
Stem cells are maintained by transcriptional programs that promote self-renewal and repress differentiation. Here, we found that the transcription factor c-Myb was essential for generating and maintaining stem cells in the CD8+ T cell memory compartment. Following viral infection, CD8+ T cells lacking Myb underwent terminal differentiation and generated fewer stem cell-like central memory cells than did Myb-sufficient T cells. c-Myb acted both as a transcriptional activator of Tcf7 (which encodes the transcription factor Tcf1) to enhance memory development and as a repressor of Zeb2 (which encodes the transcription factor Zeb2) to hinder effector differentiation. Domain-mutagenesis experiments revealed that the transactivation domain of c-Myb was necessary for restraining differentiation, whereas its negative regulatory domain was critical for cell survival. Myb overexpression enhanced CD8+ T cell memory formation, polyfunctionality and recall responses that promoted curative antitumor immunity after adoptive transfer. These findings identify c-Myb as a pivotal regulator of CD8+ T cell stemness and highlight its therapeutic potential.