| First Author | Lingel H | Year | 2017 |
| Journal | Cell Death Differ | Volume | 24 |
| Issue | 10 | Pages | 1739-1749 |
| PubMed ID | 28644433 | Mgi Jnum | J:261296 |
| Mgi Id | MGI:6151247 | Doi | 10.1038/cdd.2017.102 |
| Citation | Lingel H, et al. (2017) CTLA-4-mediated posttranslational modifications direct cytotoxic T-lymphocyte differentiation. Cell Death Differ 24(10):1739-1749 |
| abstractText | The blockade of inhibitory receptors such as CTLA-4 (CD152) is being used as immune-checkpoint therapy, offering a powerful strategy to restore effective immune responses against tumors. To determine signal components that are induced under the control of CTLA-4 we analyzed activated murine CD8(+) T cells by quantitative proteomics. Accurate mass spectrometry revealed that CTLA-4 engagement led to central changes in the phosphorylation of proteins involved in T-cell differentiation. Beside other targets, we discovered a CTLA-4-mediated induction of the translational inhibitor programmed cell death-4 (PDCD4) as a result of FoxO1 nuclear re-localization. PDCD4 further bound a distinct set of mRNAs including Glutaminase, which points out a critical role for CTLA-4 in CD8(+) T-cell metabolism. Consequently, PDCD4-deficient cytotoxic T-lymphocytes (CTLs) expressed increased amounts of otherwise repressed effector molecules and ultimately led to superior control of tumor growth in vivo. These findings reveal a novel CTLA-4-mediated pathway to attenuate CTLs and indicate the importance of post-transcriptional mechanisms in the regulation of anti-tumor immune responses. |
