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

Abstract

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.

Porcine intestinal innate lymphoid cells and lymphocyte spatial context revealed through single-cell RNA sequencing

“…Since cell clusters did not have highly overlapping expression of canonical genes characteristic of multiple cell lineages, all cells in a cluster were assigned a single cell lineage identity based on the gene expression profiles seen at the cluster level. By this rationale, 14,742 cells in 26 clusters (1, 3, 6, 7, 12, 14, 15, 17, 18, 19, 23, 24, 26, 29, 31, 32, 34, 35, 37, 41, 43, 44, 46, 47, 51, 53) were classified as T/ILC lineage lymphocytes and expressed genes such as CD3E, CD3G, CD52, and ZAP70 involved in T cell receptor (TCR) signaling or ILC intracellular signaling (Bandala-Sanchez et al, 2013; Ginaldi et al, 1998; Straus and Weiss, 1993; Tufa et al, 2020). 16,070 cells in 22 cell clusters (0, 2, 4, 5, 8, 9, 10, 11, 13, 16, 20, 21, 22, 25, 27, 28, 30, 33, 38, 39, 40, 48) were classified as B lineage lymphocytes based on expression of genes such as CD19, CD79B, MS4A1, and JCHAIN associated with B cell receptor (BCR) signaling/antibody secretion (Herrera-Uribe & Wiarda et al, 2021; Lee et al, 2021).…”

Therapeutic manipulation of innate lymphoid cells

“…Using both in vitro and in vivo developmental systems, we have demonstrated that committed human innate lymphoid progenitors (Lin -CD34 + α4/β7 + cells) develop into cells that can be distinguished by CD48 and CD52. Lin -CD34 + α4/β7 + CD48 -CD52 + cells give rise to NK cells, while Lin -CD34 + α4/β7 + CD48 + CD52cells give rise to lymphoid tissue inducer ILC3 cells, and Lin -CD34 + α4/β7 + CD48 -CD52 + cells give rise to ILC1s, ILC2s, and ILC3s (13). Modulation of both cytokines and surface receptor signaling thus directs development of differing ILC subtypes.…”

“…JCI Insight 2021;6(6):e146006 https://doi.org/10.1172/jci.insight.146006 between ILC2 and NK cell fates (13). As well, given their functional role in gastrointestinal (GI) homeostasis, we have focused on ILC3 cells, showing that ligation of death receptor 3 (DR3) on ILC3s by tumor-like antigen-1 (TL1A) costimulates in vitro-derived ILC3s and further drives expansion (14).…”

“…Patients treated with TNF-α blockade and ustekinumab also showed increases in circulating NCR + ILC3s (76), which were not observed with vedolizumab (72,76). Interestingly, the α4β7 integrin blocked by vedolizumab is known to be critical for ILC development and migration (13,77). However, the lack of change in circulating ILCs with vedolizumab suggests it is unlikely to prevent homing of ILCs from the blood to the gut (72).…”

Biology and therapeutic potential of human innate lymphoid cells

“…NK cell, LTis, ILC1, ILC2, and ILC3 were established as separate lineages [2]. Interestingly, the origin of human ILCs and how close human ILCs and NK cells are developmentally linked are still unknown despite the identification of common [4][5][6][7] and subtype-specific precursors [4,7,8]. In particular the developmental relationship between human NK cells and ILC3 is debated, as the NK cell developmental stage 3 phenotypically largely resembles ILC3 [9][10][11].…”