Heyden et al. show that chromatin organizer SATB1 is enriched in TPEX cells and limits exhausted CD8+ T cell expansion and effector differentiation in chronic infection and cancer, while maintaining functionality. SATB1 downregulation is required for the differentiation into TEX cells with high TOX and GZMB expression. SATB1 regulated effector differentiation and central memory formation of CD8+ T cells in acute and chronic infection through direct DNA binding, independent of chromatin accessibility. KO in P14(CMV gp33) T cells increased TCF1+ TPEX and TEX cells accumulation in tumors, enhanced response to ICB, and improved survival in vivo.
Contributed by Shishir Pant
ABSTRACT: CD8(+) T cells are major mediators of antiviral and antitumor immunity. During persistent antigen stimulation as in chronic infection and cancer, however, they differentiate into exhausted T cells that display impaired functionality. Precursors of exhausted T (T(PEX)) cells exhibit stem-like properties, including high proliferative, self-renewal and developmental potential, and are responsible for long-term CD8(+) T cell responses against persistent antigens. Here we identify the chromatin organizer and transcriptional regulator SATB1 as a major regulator of exhausted CD8(+) T cell differentiation. SATB1 was specifically expressed in T(PEX) cells where it limited population expansion and effector differentiation while preserving functionality of CD8(+) T cells. SATB1 downregulation was required for T(PEX) cell-to-effector cell differentiation in chronic infection and contributed to coordinated effector and memory differentiation in acute viral infection. DNA binding of SATB1 regulated gene expression both dependent and independent of chromatin accessibility. Finally, SATB1 limited antitumor CD8(+) and chimeric antigen receptor T cell immunity. Overall, our results identify SATB1 as a central regulator of precursor fate and effector differentiation of CD8(+) T cells both in infection and in cancer.
Author Info: (1) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. Institute of Molecul
Author Info: (1) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn, Bonn, Germany. (2) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (3) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (4) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (5) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (6) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. Immunogenomics and Neurodegeneration, Deutsches Zentrum fr Neurodegenerative Erkrankungen (DZNE), Bonn, Germany. (7) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (8) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (9) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (10) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (11) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (12) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (13) Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn, Bonn, Germany. (14) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (15) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (16) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (17) Immunogenomics and Neurodegeneration, Deutsches Zentrum fr Neurodegenerative Erkrankungen (DZNE), Bonn, Germany. (18) Genomics and Immunoregulation, LIMES Institute, University of Bonn, Bonn, Germany. (19) Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany. (20) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (21) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (22) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (23) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (24) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. (25) Department of Microbiology, The Biomedical Discovery Institute, Monash University, Melbourne, Victoria, Australia. (26) Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia. (27) Immunogenomics and Neurodegeneration, Deutsches Zentrum fr Neurodegenerative Erkrankungen (DZNE), Bonn, Germany. Systems Medicine, Deutsches Zentrum fr Neurodegenerative Erkrankungen (DZNE), Bonn, Germany. PRECISE Platform for Single Cell Genomics and Epigenomics, DZNE, University of Bonn, and West German Genome Center, Bonn, Germany (DZNE), Bonn, Germany. (28) Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn, Bonn, Germany. (29) Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. axel.kallies@unimelb.edu.au. Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn, Bonn, Germany. axel.kallies@unimelb.edu.au.
