Human ILCs are classically categorized into five subsets; cytotoxic CD127 CD94 NK cells and non-cytotoxic CD127 CD94 , ILC1s, ILC2s, ILC3s, and LTi cells. Here, we identify a previously unrecognized subset within the CD127 ILC population, characterized by the expression of the cytotoxic marker CD94. These CD94 ILCs resemble conventional ILC3s in terms of phenotype, transcriptome, and cytokine production, but are highly cytotoxic. IL-15 was unable to induce differentiation of CD94 ILCs toward mature NK cells. Instead, CD94 ILCs retained RORγt, CD127 and CD200R1 expression and produced IL-22 in response to IL-15. Culturing non-cytotoxic ILC3s with IL-12 induced upregulation of CD94 and cytotoxic activity, effects that were not observed with IL-15 stimulation. Thus, human helper ILCs can acquire a cytotoxic program without differentiating into NK cells.
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