| First Author | Chihara N | Year | 2018 |
| Journal | Nature | Volume | 558 |
| Issue | 7710 | Pages | 454-459 |
| PubMed ID | 29899446 | Mgi Jnum | J:265317 |
| Mgi Id | MGI:6193448 | Doi | 10.1038/s41586-018-0206-z |
| Citation | Chihara N, et al. (2018) Induction and transcriptional regulation of the co-inhibitory gene module in T cells. Nature 558(7710):454-459 |
| abstractText | 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. |
