SRP179502 PRJNA515251 GSE125099 Effector differentiation potential determined at the level of human CD8+ naïve T cell subsets [RNA-Seq] Antigen recognition by CD8+ naïve T cells induces immune activation and rapid effector differentiation that ensures elimination of virally-infected and malignant cells. While signals from the extracellular milieu and downstream of the TCR have long been known to play a crucial role, it is currently unknown whether heterogeneity within the naïve CD8+ T cell pool shapes the potency of effector differentiation. We report the identification of two discrete subsets of human CD8+ TN cells, defined by positive and negative expression of the chemokine receptor CXCR3, with different potential to generate fully-differentiated effector T cells following antigen-specific stimulation. The CXCR3+ are more abundant than the CXCR3– naïve in peripheral blood and lymphoid tissues, retain enhanced expression of effector-related genes ex vivo and display features of the T cell receptor chain repertoire indicating enhanced capacity to bind the peptide:major histocompatibility complex. Likewise, a phenotypically equivalent murine CD8+ naïve population expressing high levels of CD5, a surrogate indicator of enhanced TCR sensitivity for self, preferentially generates short-lived effector cells following infection. Our findings imply that CD8+ T cell effector differentiation potential in humans is shaped by heterogeneity in the preimmune repertoire Overall design: 18 samples GSE125099 pubmed 31740485 parent_bioproject PRJNA515252