Using single-cell expression profiling of CD4+ and CD8+ tumor-infiltrating T cells, Chihara and Madi et al. identified a co-inhibitory gene module that includes the well-known receptors PD-1, TIM-3, LAG-3, and TIGIT, as well as two novel surface molecules: activated protein C receptor (PROCR) and podoplanin (PDPN). IL-27 was found to upregulate transcription factors PRDM1 and c-MAF, which in turn redundantly upregulated the co-inhibitory module. Double knockout of PRDM1 and c-MAF almost eliminated the expression of co-inhibitory receptors, increased the presence of non-exhausted effector T cells, and reduced tumor growth in mice.

The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4(+) T cells promotes autoimmunity, whereas sustained overexpression on CD8(+) T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer(1,2). Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors. We functionally validated two new co-inhibitory receptors, activated protein C receptor (PROCR) and podoplanin (PDPN). The module of co-inhibitory receptors is co-expressed in both CD4(+) and CD8(+) T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module, and this was validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumour immunity.

Author Info: (1) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (2)

Author Info: (1) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (2) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (3) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (4) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (5) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (6) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (7) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (8) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (9) Broad Institute of MIT and Harvard, Cambridge, MA, USA. Celsius Therapeutics, Cambridge, MA, USA. (10) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (11) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (12) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (13) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (14) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. (15) Rheumatology Research Group, Center for Translational Inflammation Research, Queen Elizabeth Hospital, Birmingham, UK. (16) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. (17) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (18) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (19) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. acanderson@partners.org. Broad Institute of MIT and Harvard, Cambridge, MA, USA. acanderson@partners.org. (20) Broad Institute of MIT and Harvard, Cambridge, MA, USA. aregev@broadinstitute.org. Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. aregev@broadinstitute.org. Department of Biology, Koch Institute and Ludwig Center, Massachusetts Institute of Technology, Cambridge, MA, USA. aregev@broadinstitute.org. (21) Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. vkuchroo@evergrande.hms.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. vkuchroo@evergrande.hms.harvard.edu.

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