Defective interferon gamma production by tumor-specific cd8+ T cells is associated with 5′methylcytosine-guanine hypermethylation of interferon gamma promoter
Interferon gamma (IFNγ) supports effector responses of CD8+ cytotoxic T lymphocytes (CTLs) and is a surrogate marker for detection of antigen-specific T cells. Here, we show that tumor-specific CTL clones have impaired IFNγ expression and production upon activation. Assessment of the relationship be...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Frontiers Media
2020
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| _version_ | 1797051199003820032 |
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| author | Abd Hamid, M Yao, X Waugh, C Rosendo-Machado, S Li, C Rostron, T Frankland, J Peng, Y Dong, T |
| author_facet | Abd Hamid, M Yao, X Waugh, C Rosendo-Machado, S Li, C Rostron, T Frankland, J Peng, Y Dong, T |
| author_sort | Abd Hamid, M |
| collection | OXFORD |
| description | Interferon gamma (IFNγ) supports effector responses of CD8+ cytotoxic T lymphocytes (CTLs) and is a surrogate marker for detection of antigen-specific T cells. Here, we show that tumor-specific CTL clones have impaired IFNγ expression and production upon activation. Assessment of the relationship between IFNγ production and the 5′methylcytosine-guanine (CpG) dinucleotide methylation of the IFNγ promoter using bisulfite treatment has shown that IFNγ− CTL clones accumulates CpG hypermethylation within the promoter at key transcription factor binding sites (−186 and −54), known to be vital for transcription. We confirmed these findings using ex vivo isolated and short-term expanded bulk tumor-specific CTL lines from four cancer patients and demonstrated that IFNγ methylation inversely correlates with transcription, protein level, and cytotoxicity. Altogether, we propose that a sizeable portion of human tumor-specific CTLs are deficient in IFNγ response, contributed by CpG hypermethylation of the IFNγ promoter. Our findings have important implications for immunotherapy strategies and for methods to detect human antigen-specific T cells. |
| first_indexed | 2024-03-06T18:16:32Z |
| format | Journal article |
| id | oxford-uuid:04cc764b-02d5-4cd9-b4f4-0f1f34982251 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:16:32Z |
| publishDate | 2020 |
| publisher | Frontiers Media |
| record_format | dspace |
| spelling | oxford-uuid:04cc764b-02d5-4cd9-b4f4-0f1f349822512022-03-26T08:53:44ZDefective interferon gamma production by tumor-specific cd8+ T cells is associated with 5′methylcytosine-guanine hypermethylation of interferon gamma promoterJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:04cc764b-02d5-4cd9-b4f4-0f1f34982251EnglishSymplectic ElementsFrontiers Media2020Abd Hamid, MYao, XWaugh, CRosendo-Machado, SLi, CRostron, TFrankland, JPeng, YDong, TInterferon gamma (IFNγ) supports effector responses of CD8+ cytotoxic T lymphocytes (CTLs) and is a surrogate marker for detection of antigen-specific T cells. Here, we show that tumor-specific CTL clones have impaired IFNγ expression and production upon activation. Assessment of the relationship between IFNγ production and the 5′methylcytosine-guanine (CpG) dinucleotide methylation of the IFNγ promoter using bisulfite treatment has shown that IFNγ− CTL clones accumulates CpG hypermethylation within the promoter at key transcription factor binding sites (−186 and −54), known to be vital for transcription. We confirmed these findings using ex vivo isolated and short-term expanded bulk tumor-specific CTL lines from four cancer patients and demonstrated that IFNγ methylation inversely correlates with transcription, protein level, and cytotoxicity. Altogether, we propose that a sizeable portion of human tumor-specific CTLs are deficient in IFNγ response, contributed by CpG hypermethylation of the IFNγ promoter. Our findings have important implications for immunotherapy strategies and for methods to detect human antigen-specific T cells. |
| spellingShingle | Abd Hamid, M Yao, X Waugh, C Rosendo-Machado, S Li, C Rostron, T Frankland, J Peng, Y Dong, T Defective interferon gamma production by tumor-specific cd8+ T cells is associated with 5′methylcytosine-guanine hypermethylation of interferon gamma promoter |
| title | Defective interferon gamma production by tumor-specific cd8+ T cells is associated with 5′methylcytosine-guanine hypermethylation of interferon gamma promoter |
| title_full | Defective interferon gamma production by tumor-specific cd8+ T cells is associated with 5′methylcytosine-guanine hypermethylation of interferon gamma promoter |
| title_fullStr | Defective interferon gamma production by tumor-specific cd8+ T cells is associated with 5′methylcytosine-guanine hypermethylation of interferon gamma promoter |
| title_full_unstemmed | Defective interferon gamma production by tumor-specific cd8+ T cells is associated with 5′methylcytosine-guanine hypermethylation of interferon gamma promoter |
| title_short | Defective interferon gamma production by tumor-specific cd8+ T cells is associated with 5′methylcytosine-guanine hypermethylation of interferon gamma promoter |
| title_sort | defective interferon gamma production by tumor specific cd8 t cells is associated with 5 methylcytosine guanine hypermethylation of interferon gamma promoter |
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