KLRG1 and NKp46 discriminate subpopulations of human CD117+CRTH2− ILCs biased toward ILC2 or ILC3

Abstract

Recently, human ILCs that express CD117 and CD127 but lack CRTH2 and NKp44 have been shown to contain precursors of ILC1, ILC2, and ILC3. However, these ILCs have not been extensively characterized. We performed an unbiased hierarchical stochastic neighbor embedding (HSNE) analysis of the phenotype of peripheral blood CD117+ ILCs, which revealed the presence of three major subsets: the first expressed NKp46, the second expressed both NKp46 and CD56, and the third expressed KLRG1, but not NKp46 or CD56. Analysis of their cytokine production profiles and transcriptome revealed that NKp46+ ILCs predominantly develop into ILC3s; some of them can differentiate into ILC1/NK-like cells, but they are unable to develop into ILC2s. In contrast, KLRG1+ ILCs predominantly differentiate into ILC2s. Single-cell cultures demonstrate that KLRG1+ ILCs can also differentiate into other ILC subsets depending on the signals they receive. Epigenetic profiling of KLRG1+ ILCs is consistent with the broad differentiation potential of these cells.

Reduction of circulating innate lymphoid cell progenitors results in impaired cytokine production by innate lymphoid cells in patients with lupus nephritis

“…From this perspective, Lim et al transferred human CD117 + ILCs into BALB/c Rag2 −/− Il2rg −/− Sirpa NOD (BRGS) mice that are permissive for robust multi-lineage human hematopoietic stem cell engraftment; they found that CD117 + ILCs successfully reconstituted ILCs in various organs (lung, gut, liver, and spleen) [9]. A recent study by Nagasawa et al succeeded in verifying the presence of CD117 + ILC progenitors in peripheral organs (nasal polyps) which correspond to the circulating progenitors, but with limited potential for multi-lineage differentiation [34]. These results imply that circulating CD117 + multipotent ILC progenitors can differentiate into tissueresident ILCs to maintain tissue homeostasis.…”

OMIP‐066: Identification of Novel Subpopulations of Human Group 2 Innate Lymphoid Cells in Peripheral Blood

“…We further identified a third subpopulation that expressed skin homing receptor CCR10 (CCR10 + ILC2s) within c-Kit + ILC2s, which seemed to represent a precursor of skin ILC2s while exhibiting ILC3-like features (2). Peripheral blood CRTH2 − c-Kit + ILCs were once considered to be ILC3s (10), but recent studies have suggested that these populations are highly heterogeneous and contain progenitors for all ILC populations (4,11). Most recent study showed that an NKp46 + population and a KLRG1 + population within blood CRTH2 − c-Kit + ILCs represent progenitors biased toward ILC3s or ILC2s, respectively (4).…”

Plastic fantastic innate lymphoid cells

“…Plasticity of ILC precursors and differentiation into ILC2 and ILC3. Nagasawa, et al (2019) identify four subsets of human ILC precursor or progenitor cells based on expression of KLRG1 and NKp46, highlight discriminating transcription factors in the populations, and demonstrate their plasticity when stimulated with DL1 and polarizing cytokine environments.…”

“…In this issue of JEM , Nagasawa, et al (2019) analyze the subset of human CD127 + lymphocytes lacking mature “lineage” markers isolated from blood, tonsil, and nasal polyps. Starting with a population expressing CD117 that has previously been suggested to contain ILC progenitor populations, unsupervised clustering based on multidimensional flow cytometry analysis revealed three subsets: one characterized by expression of NKp46 and CD56, another by expression of KLRG1, and a third lacking NKp46 and KLRG1 and CD56 +/− .…”

“…Collectively, the message from this elegant work by Nagasawa, et al (2019) is that while ILCs can be pigeon-holed into “ILC2” or “ILC3” bins based on a few markers, in reality there are many transitional states blurring these distinctions, and these ILCs have remarkable plasticity that allows them to adapt to their environment to mediate appropriate biological responses.…”