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  • Induction and transcription...
    Chihara, Norio; Madi, Asaf; Kondo, Takaaki; Zhang, Huiyuan; Acharya, Nandini; Singer, Meromit; Nyman, Jackson; Marjanovic, Nemanja D; Kowalczyk, Monika S; Wang, Chao; Kurtulus, Sema; Law, Travis; Etminan, Yasaman; Nevin, James; Buckley, Christopher D; Burkett, Patrick R; Buenrostro, Jason D; Rozenblatt-Rosen, Orit; Anderson, Ana C; Regev, Aviv; Kuchroo, Vijay K

    Nature (London), 06/2018, Letnik: 558, Številka: 7710
    Journal Article

    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 . 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.