TY - JOUR
T1 - Induction and transcriptional regulation of the co-inhibitory gene module in T cells
AU - Chihara, Norio
AU - Madi, Asaf
AU - Kondo, Takaaki
AU - Zhang, Huiyuan
AU - Acharya, Nandini
AU - Singer, Meromit
AU - Nyman, Jackson
AU - Marjanovic, Nemanja D.
AU - Kowalczyk, Monika S.
AU - Wang, Chao
AU - Kurtulus, Sema
AU - Law, Travis
AU - Etminan, Yasaman
AU - Nevin, James
AU - Buckley, Christopher
AU - Burkett, Patrick R.
AU - Buenrostro, Jason D.
AU - Rozenblatt-Rosen, Orit
AU - Anderson, Ana C.
AU - Regev, Aviv
AU - Kuchroo, Vijay K.
PY - 2018/6/21
Y1 - 2018/6/21
N2 - 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.
AB - 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.
U2 - 10.1038/s41586-018-0206-z
DO - 10.1038/s41586-018-0206-z
M3 - Article
SN - 0028-0836
VL - 558
SP - 454
EP - 459
JO - Nature
JF - Nature
IS - 7710
ER -