Nat. Med. https://doi.org/10.1038/s41591-018-0204-6 (2018)

The CRISPR-Cas9 nuclease system holds great promise for therapeutic manipulation of the genome, but neutralizing immunity to this bacteria-derived product could severely limit its utility in vivo. In Nature Medicine, Schmueck-Henneresse and colleagues investigate whether the normal human population has pre-existing T cell immunity to the Cas9 component derived from Streptococcus pyogenes (SpCas9), a bacterium that causes common childhood infections. Both CD4+ effector T cells and CD8+ effector T cells respond to Cas9 in almost all donors assessed. In addition, responses to SpCas9 orthologs derived from Acidaminococcus and Staphylococcus are detected. Regulatory T cells also respond to SpCas9, which suggests that although pre-existing T cell immunity to Cas9 is prevalent in the human population, it might be mitigated by regulatory T cell–mediated suppression.