The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8+ T cells during chronic infection Journal Article
| Authors: | Staron, M. M.; Gray, S. M.; Marshall, H. D.; Parish, I. A.; Chen, J. H.; Perry, C. J.; Cui, G.; Li, M. O.; Kaech, S. M. |
| Article Title: | The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8+ T cells during chronic infection |
| Abstract: | Protein kinase B (also known as AKT) and the mechanistic target of rapamycin (mTOR) are central regulators of Tcell differentiation, proliferation, metabolism, and survival. Here, we show that during chronic murine lymphocytic choriomeningitis virus infection, activation of AKT and mTOR are impaired in antiviral cytotoxic T lymphocytes (CTLs), resulting in enhanced activity of the transcription factor FoxO1. Blockade of inhibitory receptor programmed cell death protein 1 (PD-1) invivo increased mTOR activity in virus-specific CTLs, and its therapeutic effects were abrogated by the mTOR inhibitor rapamycin. FoxO1 functioned as a transcriptional activator of PD-1 that promoted the differentiation of terminally exhausted CTLs. Importantly, FoxO1-null CTLs failed to persist and control chronic viral infection. Collectively, this study shows that CTLs adapt to persistent infection through a positive feedback pathway (PD-1→FoxO1→PD-1) that functions to both desensitize virus-specific CTLs to antigen and support their survival during chronic viral infection. |
| Keywords: | signal transduction; protein kinase b; controlled study; nonhuman; cd8+ t lymphocyte; animal cell; mouse; animal experiment; animal model; in vivo study; cell differentiation; cytotoxic t lymphocyte; positive feedback; rapamycin; transcription factor fkhr; persistent infection; programmed death 1 receptor; lymphocytic choriomeningitis virus; article; arenavirus infection |
| Journal Title: | Immunity |
| Volume: | 41 |
| Issue: | 5 |
| ISSN: | 1074-7613 |
| Publisher: | Cell Press |
| Date Published: | 2014-11-20 |
| Start Page: | 802 |
| End Page: | 814 |
| Language: | English |
| DOI: | 10.1016/j.immuni.2014.10.013 |
| PROVIDER: | scopus |
| PMCID: | PMC4270830 |
| PUBMED: | 25464856 |
| DOI/URL: | |
| Notes: | Export Date: 2 January 2015 -- Source: Scopus |
