Identification of human cytotoxic ILC3s

Abstract

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.