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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 cancer1,2. 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.

Original publication

DOI

10.1038/s41586-018-0206-z

Type

Journal article

Journal

Nature

Publication Date

06/2018

Volume

558

Pages

454 - 459

Keywords

Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Female, Gene Regulatory Networks, Immune Tolerance, Interleukin-27, Lymphocytes, Tumor-Infiltrating, Male, Melanoma, Mice, Mice, Inbred C57BL, Mice, Knockout, Positive Regulatory Domain I-Binding Factor 1, Proto-Oncogene Proteins c-maf, Receptors, Cell Surface, Reproducibility of Results, Transcription, Genetic