Human RORγt+CD34+ Cells Are Lineage-Specified Progenitors of Group 3 RORγt+ Innate Lymphoid Cells

Abstract

Group 3 innate lymphoid cells (ILC3s) are defined by the expression of the transcription factor RORγt, which is selectively required for their development. The lineage-specified progenitors of ILC3s and their site of development after birth remain undefined. Here we identified a population of human CD34(+) hematopoietic progenitor cells (HPCs) that express RORγt and share a distinct transcriptional signature with ILC3s. RORγt(+)CD34(+) HPCs were located in tonsils and intestinal lamina propria (LP) and selectively differentiated toward ILC3s. In contrast, RORγt(-)CD34(+) HPCs could differentiate to become either ILC3s or natural killer (NK) cells, with differentiation toward ILC3 lineage determined by stem cell factor (SCF) and aryl hydrocarbon receptor (AhR) signaling. Thus, we demonstrate that in humans RORγt(+)CD34(+) cells are lineage-specified progenitors of IL-22(+) ILC3s and propose that tonsils and intestinal LP, which are enriched both in committed precursors and mature ILC3s, might represent preferential sites of ILC3 lineage differentiation.

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Although much of ILC3 development is thought to take place in this compartment before birth, ILC3 may also develop from adult bone marrow ILCP and immature committed ILC3 precursors have the capacity to migrate from the bone marrow to the periphery where they undergo final maturation 14, 28, 29, 30. Similarly, human adult CD34 + haematopoietic precursor cells have been described that exhibit ROR γ t expression and an ILC3 transcriptional signature,29 while human CD34 + ROR γ t + precursors have been found in adult tonsils and the gut 28, 29, 31. Hence, in addition to the generation of fully committed mature ILC3 subsets during fetal development, further ILC3 maturation of precursors may occur locally in the tissue following birth.…”

Innate Lymphoid Cells in Graft-Versus-Host Disease

“…The development of human ILC and their progenitor(s) are less well characterized. However, recently, the human progenitor of IL‐22 producing ILC3 was described as RORγt + CD34 + hematopoietic stem cells selectively residing in the tonsil and intestinal lamina propria 8.…”

NCR+ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures

“…Recently, three subsets of ILC have been identified on the basis of their cytokine expression patterns and dependency on transcription factors [14][15][16][17] . Notably, ILC subpopulations produce an array of cytokines that in variety match those of T-helper cell subsets.…”