De novo generation of innate memory-like T cells occur early during human immune development 2254150

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Abstract Introduction Infants rely heavily on innate immunity while adaptive memory develops. A subset of T cells, termed “virtual memory” or innate-like memory T cells, bridges innate and adaptive immunity, but their emergence in early human life is unclear. Infants receiving gene therapy for X-linked severe combined immunodeficiency (SCID-X1), whose immune systems reconstitute de novo, offer a unique model to study this process. We investigated whether innate-like memory CD8+ T cells arise during immune reconstitution and defined their epigenetic, transcriptional, and functional features. Methods Longitudinal blood samples from SCID-X1 infants post—gene therapy were analyzed. Flow cytometry identified CD8+ subsets expressing NKG2A. TCR sequencing assessed clonal diversity, while DNA methylation and RNA profiling defined molecular signatures. Functional assays measured cytokine-induced, antigen-independent IFN-γ production after IL-12 and IL-18 stimulation. Results Early after gene therapy—induced immune reconstitution, infants’ peripheral blood showed a relative enrichment of innate-like memory CD8+ T cells marked by NKG2A expression. These NKG2A+ CD8 T cells displayed innate-associated transcriptional signatures and a TCR repertoire distinct from conventional naïve/memory subsets. DNA methylation profiling confirmed a subset-specific epigenetic signature, including open (poised) regions at effector genes, consistent with readiness for rapid response. Functionally, when stimulated ex vivo with IL-12+IL-18, NKG2A+ T cells produced IFN-γ in an antigen-independent fashion, indicative of innate-like responsiveness. Together, these features distinguish them from conventional antigen-driven memory CD8 T cells. Conclusion Innate-like memory CD8+ T cells (NKG2A+ “virtual memory” T cells) arise early in human life during immune reconstitution and are epigenetically and transcriptionally primed for rapid, antigen-independent effector responses. Funding Source NIH (R01AI114442; R01CA237311; P01-HL053749; U54AI082973;P01AI138962), The ASSISI Foundation of Memphis, AlexLemonade Stand, SU2C, Key for a Cure Foundation, NRSA(F32-CA250155), CIRM (CLIN2-10830; CLIN2-09504), and theAmerican Lebanese Syrian Associated Topic Categories Hematopoiesis and Immune System Development (HEM)

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