CXCR3 Identifies Human Naive CD8⁺ T Cells with Enhanced Effector Differentiation Potential

In mice, the ability of naive T (T_N) cells to mount an effector response correlates with TCR sensitivity for self-derived Ags, which can be quantified indirectly by measuring surface expression levels of CD5. Equivalent findings have not been reported previously in humans. We identified two discrete subsets of human CD8⁺ T_N cells, defined by the absence or presence of the chemokine receptor CXCR3. The more abundant CXCR3⁺ T_N cell subset displayed an effector-like transcriptional profile and expressed TCRs with physicochemical characteristics indicative of enhanced interactions with peptide-HLA class I Ags. Moreover, CXCR3⁺ T_N cells frequently produced IL-2 and TNF in response to nonspecific activation directly ex vivo and differentiated readily into Ag-specific effector cells in vitro. Comparative analyses further revealed that human CXCR3⁺ T_N cells were transcriptionally equivalent to murine CXCR3⁺ T_N cells, which expressed high levels of CD5. These findings provide support for the notion that effector differentiation is shaped by heterogeneity in the preimmune repertoire of human CD8⁺ T cells.