Regulation and function of innate-like T cells
KLRB1, encoding for CD161, is one of the most favourable prognostic pan-cancer genes. It is expressed by NK- and T-cell subsets, particularly by innate-like T cells such as MAIT and γδT cells. CD161-expressing T-cell subsets share a transcriptional and functional phenotype, including the ability to...
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| Format: | Thesis |
| Language: | English |
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2021
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| _version_ | 1824458718051303424 |
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| author | Hagel, JP |
| author2 | Klenerman, P |
| author_facet | Klenerman, P Hagel, JP |
| author_sort | Hagel, JP |
| collection | OXFORD |
| description | KLRB1, encoding for CD161, is one of the most favourable prognostic pan-cancer genes. It is expressed by NK- and T-cell subsets, particularly by innate-like T cells such as MAIT and γδT cells. CD161-expressing T-cell subsets share a transcriptional and functional phenotype, including the ability to be activated by cytokines in a T-cell receptor-independent manner, similar to NK cells. The regulation and function of CD161-expressing cells as well as their role in cancer is not fully understood, however. In this study, an imaging-based high-content cytometry method, called ChipCytometry, was developed as a truly viable technique to identify and deeply phenotype CD161-positive cell types in blood and tissue. Novel mechanisms for the activation of CD161-expressing T cells were discovered by stimulation with the relatively underexplored cytokine IL-32. The ability of CD161-expressing T cells to also express IL-32 upon activation was demonstrated in vitro. To elucidate the role of IL-32 in disease, a pan-cancer IL32 gene signature was generated from The Cancer Genome Atlas (TCGA) RNA-seq data. The IL32 signature genes were associated with immune response- and T-cell activation-related pathways. Single-cell RNA-seq data from breast cancer-derived immune cells showed that IL32 gene expression and the expression of the most significant IL32 signature genes were strongly associated with innate-like T cells, including MAIT and γδT cells, in addition to memory T cells and Tregs. Finally, estimated immune cell fractions within TCGA data revealed that the favourable prognostic association of CD161 across cancers was attributable to multiple CD161-expressing cell types. These include NK cells, γδT cells, tissue-resident memory T cells, cytotoxic T cells and the still poorly studied T follicular helper cells in cancer. In summary, the findings of this study expand the knowledge of the regulation and function of CD161-expressing immune subsets and their role in cancer, setting the stage for their use as a clinical biomarker or in cancer immunotherapy. |
| first_indexed | 2024-03-07T02:12:49Z |
| format | Thesis |
| id | oxford-uuid:a13c68dd-3fe7-4b8c-ad32-506045409f63 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2025-02-19T04:30:20Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | oxford-uuid:a13c68dd-3fe7-4b8c-ad32-506045409f632025-01-02T09:46:46ZRegulation and function of innate-like T cellsThesishttp://purl.org/coar/resource_type/c_db06uuid:a13c68dd-3fe7-4b8c-ad32-506045409f63EnglishHyrax Deposit2021Hagel, JPKlenerman, PBuffa, FWillberg, CKLRB1, encoding for CD161, is one of the most favourable prognostic pan-cancer genes. It is expressed by NK- and T-cell subsets, particularly by innate-like T cells such as MAIT and γδT cells. CD161-expressing T-cell subsets share a transcriptional and functional phenotype, including the ability to be activated by cytokines in a T-cell receptor-independent manner, similar to NK cells. The regulation and function of CD161-expressing cells as well as their role in cancer is not fully understood, however. In this study, an imaging-based high-content cytometry method, called ChipCytometry, was developed as a truly viable technique to identify and deeply phenotype CD161-positive cell types in blood and tissue. Novel mechanisms for the activation of CD161-expressing T cells were discovered by stimulation with the relatively underexplored cytokine IL-32. The ability of CD161-expressing T cells to also express IL-32 upon activation was demonstrated in vitro. To elucidate the role of IL-32 in disease, a pan-cancer IL32 gene signature was generated from The Cancer Genome Atlas (TCGA) RNA-seq data. The IL32 signature genes were associated with immune response- and T-cell activation-related pathways. Single-cell RNA-seq data from breast cancer-derived immune cells showed that IL32 gene expression and the expression of the most significant IL32 signature genes were strongly associated with innate-like T cells, including MAIT and γδT cells, in addition to memory T cells and Tregs. Finally, estimated immune cell fractions within TCGA data revealed that the favourable prognostic association of CD161 across cancers was attributable to multiple CD161-expressing cell types. These include NK cells, γδT cells, tissue-resident memory T cells, cytotoxic T cells and the still poorly studied T follicular helper cells in cancer. In summary, the findings of this study expand the knowledge of the regulation and function of CD161-expressing immune subsets and their role in cancer, setting the stage for their use as a clinical biomarker or in cancer immunotherapy. |
| spellingShingle | Hagel, JP Regulation and function of innate-like T cells |
| title | Regulation and function of innate-like T cells |
| title_full | Regulation and function of innate-like T cells |
| title_fullStr | Regulation and function of innate-like T cells |
| title_full_unstemmed | Regulation and function of innate-like T cells |
| title_short | Regulation and function of innate-like T cells |
| title_sort | regulation and function of innate like t cells |
| work_keys_str_mv | AT hageljp regulationandfunctionofinnateliketcells |