Memory-like T cells emerge early in circulation after gene therapy for SCID-X1 [scRNA-seq]

Studying the emerging immune system after successful gene therapy for X-linked severe combined immunodeficiency (SCID-X1) in infants provides a unique opportunity to characterize human T cell development. Here we report our longitudinal analysis of T cells isolated from the peripheral blood of SCID-X1 patients after treatment with gene-transduced autologous CD34+ cells. We observed an early enrichment of memory-like T cells, which was intriguing given that newly generated T cells were unlikely to have previously encountered their cognate antigen. Single-cell RNA sequencing of the emerging and established T cell pool identified a subset of memory-like cells enriched for NKG2A expression that contained innate-associated transcriptional profiles. Genome-wide epigenetic profiling of the de novo memory-like NKG2A+ T cell subset confirmed an epigenetic permissivity of this locus along with programs indicating a poised effector response. Consistent with the epigenetic profile, ex vivo stimulation of NKG2A+ T cells with IL-12 and IL-18 resulted in antigen-independent IFNg expression. Collectively, these data suggest that NKG2A+ innate memory-like T cells develop early in human life and are epigenetically poised to rapidly elicit effector cytokines in an antigen-independent manner.