Human innate lymphoid cell precursors express CD48 that modulates ILC differentiation through 2B4 signaling

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Science Immunology  20 Nov 2020:
Vol. 5, Issue 53, eaay4218
DOI: 10.1126/sciimmunol.aay4218

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Differentiation distinctions

Murine innate lymphoid cell (ILC) differentiation has been studied in detail, but human ILC development is less well understood because of differences in surface markers between species. Tufa et al. show that human common innate lymphoid progenitors (CILPs), characterized as CD34+CD117+α4β7+Lin, express CD48 and CD52 and can give rise to NK cell progenitors (NKPs) and ILC progenitors. CD34+CD117+α4β7+LinCD48CD52+ and CD34+CD117+α4β7+LinCD48+CD52+ NKP differentiated into two different NK cell subsets under in vitro differentiation conditions. ILCPs within the CD34+CD117+α4β7+LinCD48+CD52+ subset could differentiate into ILC1s, ILC2s, and NCR+ ILC3s, but CD34+CD117+α4β7+LinCD48+CD52 ILCPs gave rise to a different ILC3 subset with lymphoid tissue inducer–like properties. Ligation of the 2B4 receptor by CD48 was needed for ILC2 development, and these results define a role for CD48 in human ILC differentiation.


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+LinCD48CD52+ and CD34+CD117+α4β7+LinCD48+CD52+ NKPs, respectively. Independent of NKPs, ILCPs exist in the CD34+CD117+α4β7+LinCD48+CD52+ subset and give rise to ILC1s, ILC2s, and NCR+ ILC3s, whereas CD34+CD117+α4β7+LinCD48+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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