Induction and transcriptional regulation of the co-inhibitory gene module in T cells
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 dysfu...
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| Format: | Article |
| Language: | English |
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Springer Nature
2020
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| Online Access: | https://hdl.handle.net/1721.1/125051 |
| _version_ | 1826204835921264640 |
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| author | Regev, Aviv |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Regev, Aviv |
| author_sort | Regev, Aviv |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:02:09Z |
| format | Article |
| id | mit-1721.1/125051 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:02:09Z |
| publishDate | 2020 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | mit-1721.1/1250512022-10-01T12:40:39Z Induction and transcriptional regulation of the co-inhibitory gene module in T cells Regev, Aviv Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT 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. 2020-05-06T15:28:44Z 2020-05-06T15:28:44Z 2018-06 2020-01-28T17:18:40Z Article http://purl.org/eprint/type/JournalArticle 0028-0836 https://hdl.handle.net/1721.1/125051 Chihara, Norio et al. “Induction and transcriptional regulation of the co-inhibitory gene module in T cells.” Nature 558 (2018): 454-459 © 2018 The Author(s) en 10.1038/S41586-018-0206-Z Nature Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Springer Nature PMC |
| spellingShingle | Regev, Aviv Induction and transcriptional regulation of the co-inhibitory gene module in T cells |
| title | Induction and transcriptional regulation of the co-inhibitory gene module in T cells |
| title_full | Induction and transcriptional regulation of the co-inhibitory gene module in T cells |
| title_fullStr | Induction and transcriptional regulation of the co-inhibitory gene module in T cells |
| title_full_unstemmed | Induction and transcriptional regulation of the co-inhibitory gene module in T cells |
| title_short | Induction and transcriptional regulation of the co-inhibitory gene module in T cells |
| title_sort | induction and transcriptional regulation of the co inhibitory gene module in t cells |
| url | https://hdl.handle.net/1721.1/125051 |
| work_keys_str_mv | AT regevaviv inductionandtranscriptionalregulationofthecoinhibitorygenemoduleintcells |