ALT Treating a Primary Immunodeficiency with CRISPR. Familial hemophagocytic lymphohistiocytosis (FHL) is a range of inherited, sometimes fatal, inflammatory diseases caused by loss-of-function mutations in the cytotoxic machinery of immune cells. Li et al. developed an adeno-associated virus (AAV)–based CRISPR–Cas9 system combined with nonhomologous end joining (NHEJ) inhibition to repair memory T cells from perforin (Prf1)-deficient mice as well as from pediatric patients with FHL2 (PRF1 deficiency) or FHL3 (Munc13-4/UNC13D deficiency). Repaired mouse T cells could then prevent or cure FHL2-like disease in Prf1-knockout mice triggered by Epstein–Barr virus (EBV)–driven B cell hyperproliferation. This month’s cover illustration depicts CRISPR–Cas9–mediated repair of a cytotoxic T cell (red), which allows it to secrete normal cytotoxic granules (pink) and effectively kill virally infected B cells (blue).