TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance Journal Article
| Authors: | Thomas, D. A.; Massague, J. |
| Article Title: | TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance |
| Abstract: | Tumors escape from immune surveillance by producing the immunosuppressive cytokine TGF-β. However, the mechanism by which TGF-β inhibits T cell-mediated tumor clearance in vivo is unknown. We demonstrate that TGF-β acts on cytotoxic T lymphocytes (CTLs) to specifically inhibit the expression of five cytolytic gene products - namely, perforin, granzyme A, granzyme B, Fas ligand, and interferon γ - which are collectively responsible for CTL-mediated tumor cytotoxicity. Repression of granzyme B and interferon-γ involves binding of TGF-β-activated Smad and ATF1 transcription factors to their promoter regions, indicating direct and selective regulation by the TGF-β/Smad pathway. Neutralization of systemic TGF-β in mice enables tumor clearance with restoration of cytotoxic gene expression in antigen-specific CTLs in vivo. We suggest that TGF-β suppresses CTL function in vivo through an anticytotoxic program of transcriptional repression. Copyright © 2005 Elsevier Inc. |
| Keywords: | controlled study; protein expression; unclassified drug; promoter region; nonhuman; cell proliferation; blood proteins; animal cell; mouse; animals; mice; cell function; gene expression; gene expression profiling; smad protein; transforming growth factor beta; fas ligand; protein binding; gene product; transcription factor; cytotoxicity; cell line, tumor; animalia; gene expression regulation, neoplastic; granzyme b; cytokine; serine endopeptidases; gamma interferon; antigen specificity; cytotoxic t lymphocyte; t-lymphocytes, cytotoxic; smad proteins; perforin; cytotoxicity, immunologic; immunosuppressive treatment; immunosurveillance; interleukin-2; granzymes; enzyme repression; activating transcription factor 1; tumor escape; interferon type ii; activating transcription factors; granzyme a |
| Journal Title: | Cancer Cell |
| Volume: | 8 |
| Issue: | 5 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2005-11-01 |
| Start Page: | 369 |
| End Page: | 380 |
| Language: | English |
| DOI: | 10.1016/j.ccr.2005.10.012 |
| PUBMED: | 16286245 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 213" - "Export Date: 24 October 2012" - "CODEN: CCAEC" - "Source: Scopus" |
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