From the PBMCs of healthy volunteers, Correia et al. uncovered a unique subset of CD8+ T cells that express the activating natural killer receptor NKp30, display a diverse TCR repertoire, and exhibit a naive phenotype with few exhaustion markers. Treatment of NKp30-CD8+ T cells with IL-15 led to surface expression of functional NKp30, dependent on upregulation of the FcεRIγ adaptor, and reprogramming to an innate-like gene expression profile. IL-15 further differentiated this subset into effector memory NKp30hiCD8+ T cells with an NK-like phenotype; these cells efficiently killed tumor cells in vitro and controlled tumor growth in a xenograft mouse model of melanoma.
CD8(+) T cells are considered prototypical cells of adaptive immunity. Here, we uncovered a distinct CD8(+) T cell population expressing the activating natural killer (NK) receptor NKp30 in the peripheral blood of healthy individuals. We revealed that IL-15 could de novo induce NKp30 expression in a population of CD8(+) T cells and drive their differentiation toward a broad innate transcriptional landscape. The adaptor FcepsilonRIgamma was concomitantly induced and was shown to be crucial to enable NKp30 cell-surface expression and function in CD8(+) T cells. FcepsilonRIgamma de novo expression required promoter demethylation and was accompanied by acquisition of the signaling molecule Syk and the "innate" transcription factor PLZF. IL-15-induced NKp30(+)CD8(+) T cells exhibited high NK-like antitumor activity in vitro and were able to synergize with T cell receptor signaling. Importantly, this population potently controlled tumor growth in a preclinical xenograft mouse model. Our study, while blurring the borders between innate and adaptive immunity, reveals a unique NKp30(+)FcepsilonRIgamma(+)CD8(+) T cell population with high antitumor therapeutic potential.