De novo generation of innate memory-like T cells occur early during human immune development 9039

Description The ability to study T cell development in a human model which mimics the establishment of the immune system is a valuable prospect. Our successful gene therapy clinical trial for X-linked severe combined immunodeficiency (SCID-X1) in infants offers such a unique opportunity. By conducting a longitudinal analysis of T cells isolated from peripheral blood of these SCID-X1 patients after treatment we saw along with naïve cells the early enrichment of memory-like T cells. This is intriguing given that newly generated T cells were unlikely to have encountered their cognate antigen. Single-cell RNA sequencing of the emerging and established T cell pool identifies these cells as 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 distinct from naïve cells. Consistent with the epigenetic profile, ex vivo stimulation of NKG2A+ T cells with IL-12/IL-18 resulted in antigen-independent IFNγ expression a hallmark of innate memory T cells. Collectively, these data shows that these innate memory-like T cells that are epigenetically poised to rapidly elicit effector cytokines do develop early in human life. Funding Sources NIH(R01AI114442; R01CA237311; P01-HL053749; U54AI082973; P01AI138962), The ASSISI Foundation of Memphis, Alex Lemonade Stand, SU2C, Key for a Cure Foundation, NRSA (F32-CA250155), CIRM (CLIN2-10830; CLIN2-09504), and the American Lebanese Syrian Associated Charities (ALSAC).