Interleukin-12 and -23 Control Plasticity of CD127+ Group 1 and Group 3 Innate Lymphoid Cells in the Intestinal Lamina Propria

Abstract

Human group 1 ILCs consist of at least three phenotypically distinct subsets, including NK cells, CD127(+) ILC1, and intraepithelial CD103(+) ILC1. In inflamed intestinal tissues from Crohn's disease patients, numbers of CD127(+) ILC1 increased at the cost of ILC3. Here we found that differentiation of ILC3 to CD127(+) ILC1 is reversible in vitro and in vivo. CD127(+) ILC1 differentiated to ILC3 in the presence of interleukin-2 (IL-2), IL-23, and IL-1β dependent on the transcription factor RORγt, and this process was enhanced in the presence of retinoic acid. Furthermore, we observed in resection specimen from Crohn's disease patients a higher proportion of CD14(+) dendritic cells (DC), which in vitro promoted polarization from ILC3 to CD127(+) ILC1. In contrast, CD14(-) DCs promoted differentiation from CD127(+) ILC1 toward ILC3. These observations suggest that environmental cues determine the composition, function, and phenotype of CD127(+) ILC1 and ILC3 in the gut.

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…3). Complimentary findings in human tissue samples demonstrated reversible conversion between NCR + ILC3 subsets and ILC1‐like ‘ex‐ILC3’ dependent on the local cytokine milieu, which was determined by tissue‐resident myeloid populations 72, 73. These findings demonstrate significant plasticity among CCR6 − ILC3, which is both tuneable and reversible.…”

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…Furthermore, ILC1s accumulate in the inflamed intestine of CD patients 30. There also seems to be some plasticity between ILC1 and ILC3 cells 32, 33. Thus, ILCs secreting both IFN γ and IL‐17 in response to IL‐23, or IFN γ and IL‐22 in response to IL‐12+IL‐18 have been reported 26, 34.…”

Emerging roles of innate lymphoid cells in inflammatory diseases: Clinical implications

“…35 Human data are scarce, but in mice, IL-17A producing ILC3s were implicated in obesity-induced asthma, 51,52 indicating a possible role for IL-1b 51 as this cytokine can stimulate both ILC2s and ILC3s. 6,53,54 In a pilot study, IL-17A-producing lineage negative cells in BAL were demonstrated to be enriched in patients with severe asthma. 51 So far, no other studies have been performed analyzing ILC subsets in patients with Th2-low asthma.…”

“…5,13,54,84,90,91 In this manner ILCs are potentially interfering with the maintenance of the epithelial barrier, induction of antimicrobial peptides and wound healing. 13 The enhanced frequency of IFN-c-producing ILC1s directly affects the epithelial barrier, amplifying its disruption.…”

“…5,13,54,84,90 • Increased infiltration of ILC1s was found in rectal biopsies from wheat-challenged NCWS patients. ILC2s.…”