ABSTRACT
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.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Gene Expression Regulation , Homeodomain Proteins/genetics , Infections/etiology , Single-Cell Analysis , Animals , Biomarkers , Chromatin Immunoprecipitation , Epigenesis, Genetic , Gene Expression Profiling , High-Throughput Nucleotide Sequencing , Homeodomain Proteins/metabolism , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Immunologic Memory , Infections/metabolism , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/virology , Lymphocytic choriomeningitis virus/immunology , Mice , Time Factors , TranscriptomeABSTRACT
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.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Melanoma, Experimental/immunology , MicroRNAs/metabolism , Skin Neoplasms/immunology , Transcription Factors/metabolism , Adoptive Transfer/methods , Animals , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/transplantation , Cell Differentiation/genetics , Cell Differentiation/immunology , Cellular Senescence/genetics , Cellular Senescence/immunology , Epigenesis, Genetic/immunology , Female , Gene Expression Regulation, Neoplastic , Humans , Melanoma, Experimental/genetics , Melanoma, Experimental/therapy , Mice , Mice, Inbred C57BL , Mice, Knockout , Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases/genetics , Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases/metabolism , Polycomb Repressive Complex 2/immunology , Polycomb Repressive Complex 2/metabolism , Skin Neoplasms/genetics , Skin Neoplasms/therapy , Transcription Factors/genetics , Transcription Factors/immunologyABSTRACT
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.