Innate lymphoid cells (ILCs) develop from common lymphoid progenitors (CLPs), which further differentiate into the common ILC progenitor (CILP) that can give rise to both ILCs and natural killer (NK) cells. Murine ILC intermediates have recently been characterized, but the human counterparts and their developmental trajectories have not yet been identified, largely due to the lack of homologous surface receptors in both organisms. Here, we show that human CILPs (CD34⁺CD117⁺α4β7⁺Lin^-) acquire CD48 and CD52, which define NK progenitors (NKPs) and ILC precursors (ILCPs). Two distinct NK cell subsets were generated in vitro from CD34⁺CD117⁺α4β7⁺Lin^-CD48^-CD52⁺ and CD34⁺CD117⁺α4β7⁺Lin^-CD48⁺CD52⁺ NKPs, respectively. Independent of NKPs, ILCPs exist in the CD34⁺CD117⁺α4β7⁺Lin^-CD48⁺CD52⁺ subset and give rise to ILC1s, ILC2s, and NCR⁺ ILC3s, whereas CD34⁺CD117⁺α4β7⁺Lin^-CD48⁺CD52^- ILCPs give rise to a distinct subset of ILC3s that have lymphoid tissue inducer (LTi)-like properties. In addition, CD48-expressing CD34⁺CD117⁺α4β7⁺Lin^- precursors give rise to tissue-associated ILCs in vivo. We also observed that the interaction of 2B4 with CD48 induced differentiation of ILC2s, and together, these findings show that expression of CD48 by human ILCPs modulates ILC differentiation.

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