Abstract
In mice, the ability of naive T (TN) 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+ TN cells, defined by the absence or presence of the chemokine receptor CXCR3. The more abundant CXCR3+ TN 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+ TN 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+ TN cells were transcriptionally equivalent to murine CXCR3+ TN 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.
Highlights
We found that TCR rearrangement excision circle (TREC) were ∼2-fold more common in TNR32 cells compared with TNR3+ cells, ∼4-fold more common in TNR32 cells compared with stem cell–like TMEM (TSCM) cells [9], and ∼25-fold more common in TNR32 cells compared with memory T (TMEM) cells (Fig. 2A)
In accordance with these data, genes upregulated in murine TNR3+ versus CD5lo (n = 221; false discovery rate (FDR), 0.0001) and murine TNR3+ versus CD5hi cells (n = 37; FDR, 0.0001) were preferentially enriched in human TNR3+ versus TNR32 cells, indicating close transcriptional parallels between TNR3+ cells in different species (Figs. 3C, 5E). It has become apparent in recent years that the classically defined naive T (TN) cell pool incorporates subpopulations of cells with memorylike properties, including TSCM cells [9, 51] and memory cell with a TN-like phenotype (TMNP) cells [58]
We found that truly naive T cells can exhibit distinct characteristics, both in humans and in mice
Summary
A recent study identified a rare population of memory cells with a TN-like phenotype (TMNP) that expressed high levels of CD49d and CXCR3 and rapidly produced IFN-g in response to stimulation with PMA and ionomycin [58].
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