IL-12 drives the expression of the inhibitory receptor NKG2A on human tumor-reactive CD8 T cells
Abstract Blockade of NKG2A/HLA-E interaction is a promising strategy to unleash the anti-tumor response. Yet the role of NKG2A+ CD8 T cells in the anti-tumor response and the regulation of NKG2A expression on human tumor-infiltrating T cells are still poorly understood. Here, by performing CITE-seq...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54420-w |
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| author | Olivier Fesneau Kimberly A. Samson Wesley Rosales Bretton Jones Tarsem Moudgil Bernard A. Fox Venkatesh Rajamanickam Thomas Duhen |
| author_facet | Olivier Fesneau Kimberly A. Samson Wesley Rosales Bretton Jones Tarsem Moudgil Bernard A. Fox Venkatesh Rajamanickam Thomas Duhen |
| author_sort | Olivier Fesneau |
| collection | DOAJ |
| description | Abstract Blockade of NKG2A/HLA-E interaction is a promising strategy to unleash the anti-tumor response. Yet the role of NKG2A+ CD8 T cells in the anti-tumor response and the regulation of NKG2A expression on human tumor-infiltrating T cells are still poorly understood. Here, by performing CITE-seq on T cells derived from head and neck squamous cell carcinoma and colorectal cancer, we show that NKG2A expression is induced on CD8 T cells differentiating into cytotoxic, CD39+CD103+ double positive (DP) cells, a phenotype associated with tumor-reactive T cells. This developmental trajectory leads to TCR repertoire overlap between the NKG2A– and NKG2A+ DP CD8 T cells, suggesting shared antigen specificities. Mechanistically, IL-12 is essential for the expression of NKG2A on CD8 T cells in a CD40/CD40L- dependent manner, in conjunction with TCR stimulation. Our study thus reveals that NKG2A is induced by IL-12 on human tumor-reactive CD8 T cells exposed to a TGF-β-rich environment, highlighting an underappreciated immuno-regulatory feedback loop dependent on IL-12 stimulation. |
| format | Article |
| id | doaj-art-be9c79b9ec094fa6a12f7efd27173914 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-be9c79b9ec094fa6a12f7efd271739142024-11-24T12:35:02ZengNature PortfolioNature Communications2041-17232024-11-0115111810.1038/s41467-024-54420-wIL-12 drives the expression of the inhibitory receptor NKG2A on human tumor-reactive CD8 T cellsOlivier Fesneau0Kimberly A. Samson1Wesley Rosales2Bretton Jones3Tarsem Moudgil4Bernard A. Fox5Venkatesh Rajamanickam6Thomas Duhen7Earle A. Chiles Research Institute, Providence Cancer InstituteEarle A. Chiles Research Institute, Providence Cancer InstituteEarle A. Chiles Research Institute, Providence Cancer InstituteEarle A. Chiles Research Institute, Providence Cancer InstituteEarle A. Chiles Research Institute, Providence Cancer InstituteEarle A. Chiles Research Institute, Providence Cancer InstituteEarle A. Chiles Research Institute, Providence Cancer InstituteEarle A. Chiles Research Institute, Providence Cancer InstituteAbstract Blockade of NKG2A/HLA-E interaction is a promising strategy to unleash the anti-tumor response. Yet the role of NKG2A+ CD8 T cells in the anti-tumor response and the regulation of NKG2A expression on human tumor-infiltrating T cells are still poorly understood. Here, by performing CITE-seq on T cells derived from head and neck squamous cell carcinoma and colorectal cancer, we show that NKG2A expression is induced on CD8 T cells differentiating into cytotoxic, CD39+CD103+ double positive (DP) cells, a phenotype associated with tumor-reactive T cells. This developmental trajectory leads to TCR repertoire overlap between the NKG2A– and NKG2A+ DP CD8 T cells, suggesting shared antigen specificities. Mechanistically, IL-12 is essential for the expression of NKG2A on CD8 T cells in a CD40/CD40L- dependent manner, in conjunction with TCR stimulation. Our study thus reveals that NKG2A is induced by IL-12 on human tumor-reactive CD8 T cells exposed to a TGF-β-rich environment, highlighting an underappreciated immuno-regulatory feedback loop dependent on IL-12 stimulation.https://doi.org/10.1038/s41467-024-54420-w |
| spellingShingle | Olivier Fesneau Kimberly A. Samson Wesley Rosales Bretton Jones Tarsem Moudgil Bernard A. Fox Venkatesh Rajamanickam Thomas Duhen IL-12 drives the expression of the inhibitory receptor NKG2A on human tumor-reactive CD8 T cells Nature Communications |
| title | IL-12 drives the expression of the inhibitory receptor NKG2A on human tumor-reactive CD8 T cells |
| title_full | IL-12 drives the expression of the inhibitory receptor NKG2A on human tumor-reactive CD8 T cells |
| title_fullStr | IL-12 drives the expression of the inhibitory receptor NKG2A on human tumor-reactive CD8 T cells |
| title_full_unstemmed | IL-12 drives the expression of the inhibitory receptor NKG2A on human tumor-reactive CD8 T cells |
| title_short | IL-12 drives the expression of the inhibitory receptor NKG2A on human tumor-reactive CD8 T cells |
| title_sort | il 12 drives the expression of the inhibitory receptor nkg2a on human tumor reactive cd8 t cells |
| url | https://doi.org/10.1038/s41467-024-54420-w |
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