Innate-like memory T cells rapidly emerge in humans after gene therapy for SCID-X1

Virtual memory T cells, possessing features of innate immune cells, represent a developmental continuum between innate and adaptive immunity. Here, we describe the genesis of virtual memory T cells during early human life. A longitudinal analysis of peripheral T cells after gene therapy for X-linked severe combined immunodeficiency (SCID-X1) in infants revealed an early enrichment of innate-like memory CD8⁺ T cells that expressed NKG2A, innate-associated transcriptional profiles, and a distinct T cell receptor (TCR) repertoire. Genome-wide DNA methylation profiling of the de novo innate-like memory NKG2A⁺ T cell subset confirmed a subset-specific epigenetic signature that included a poised effector response. Furthermore, ex vivo stimulation of NKG2A⁺ T cells with IL-12 and IL-18 resulted in antigen-independent interferon gamma (IFNγ) expression. Collectively, these data indicate that NKG2A⁺ innate-like memory T cells develop early in human life and are epigenetically poised to rapidly elicit effector cytokines in an antigen-independent manner.