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.
Author Info: (1) Group of Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; m.correia@dkfz.de. Department of Immunobiochemistry, Centre for Biomedicine and Medic
Author Info: (1) Group of Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; m.correia@dkfz.de. Department of Immunobiochemistry, Centre for Biomedicine and Medical Technology (CBTM), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany. (2) Group of Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Department of Immunobiochemistry, Centre for Biomedicine and Medical Technology (CBTM), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany. (3) Group of Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (4) Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (5) Division of Rheumatology, Department of Medicine V, Heidelberg University, 69120 Heidelberg, Germany. (6) Division of Rheumatology, Department of Medicine V, Heidelberg University, 69120 Heidelberg, Germany. (7) Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany. German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. (8) Group of Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Department of Immunobiochemistry, Centre for Biomedicine and Medical Technology (CBTM), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany. European Center for Angioscience (ECAS), University Medical Center and Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
