Stage-specific CAR-mediated signaling generates naïve-like, TCR-null CAR T cells from induced pluripotent stem cells.

Genetically modified, induced pluripotent stem cells (iPSCs) offer a promising allogeneic source for the generation of functionally enhanced, chimeric antigen receptor (CAR) T cells. However, the signaling of CARs during early T cell development and the removal of the endogenous T cell receptor required to prevent alloreactivity pose significant challenges to the production of mature conventional CAR T cells from iPSCs. Here, we show that TCR-null, CD8αβ CAR T cells can be efficiently generated from iPSCs by engineering stage-specific onset of CAR expression and signaling to both permit conventional T cell development and to induce efficient positive selection.

The fidelity of transcription in human cells.

To determine the error rate of transcription in human cells, we analyzed the transcriptome of H1 human embryonic stem cells with a circle-sequencing approach that allows for high-fidelity sequencing of the transcriptome. These experiments identified approximately 100,000 errors distributed over every major RNA species in human cells. Our results indicate that different RNA species display different error rates, suggesting that human cells prioritize the fidelity of some RNAs over others.

Genome-wide surveillance of transcription errors in response to genotoxic stress.

Mutagenic compounds are a potent source of human disease. By inducing genetic instability, they can accelerate the evolution of human cancers or lead to the development of genetically inherited diseases. Here, we show that in addition to genetic mutations, mutagens are also a powerful source of transcription errors.