A Progenitor Cell Expressing Transcription Factor RORγt Generates All Human Innate Lymphoid Cell Subsets

Abstract

Summary The current model of murine innate lymphoid cell (ILC) development holds that mouse ILCs are derived downstream of the common lymphoid progenitor through lineage-restricted progenitors. However, corresponding lineage-restricted progenitors in humans have yet to be discovered. Here we identified a progenitor population in human secondary lymphoid tissues (SLTs) that expressed the transcription factor, RORγt, and was unique in its ability to generate all known ILC subsets, including natural killer (NK) cells, but not other leukocyte populations. In contrast to murine fate-mapping data, which indicate that only ILC3 cells express Rorγt, these human progenitor cells as well as human peripheral blood NK cells and all mature ILC populations expressed RORγt. Thus, all human ILCs can be generated through an RORγt+ developmental pathway from a common progenitor in SLTs. These findings help establish the developmental signals and pathways involved in human ILC development.

Interleukins 12 and 15 induce cytotoxicity and early NK-cell differentiation in type 3 innate lymphoid cells

“…16 17,18 Moreover, RORgt-expressing precursors might give rise to NK cells. 18,19 Therefore, these studies, as a second line of evidence, also suggest that cells with phenotypic and functional similarities to ILC3s can give rise to NK cells. To investigate this question in more detail, we isolated ILC3s from pediatric tonsils and secondary lymphoid and intestinal tissues of mice with reconstituted human immune system components and exposed them to proinflammatory cytokines.…”

“…The findings that human NK cells can be derived from RORgtexpressing precursors 18,19 and the controversial existence of an ILC1 population distinct from NK cells in humans 11 suggest fundamental species differences in ILC biology [25][26][27] and the need for a better experimental model to study human ILC biology. To that end, we characterized ILCs, specifically ILC3s and NK cells, in NOD-scid Il2rg null mice engrafted with human CD34 1 hematopoietic progenitor cells, denoted as huNSG mice (human reconstitution shown in supplemental Figure 1).…”

A functional DC cross talk promotes human ILC homeostasis in humanized mice

“…16,24,37 A second mechanism may involve direct effects of Flt3L on CD135 1 lymphoid committed precursors that are upstream of human ILC or NK precursors. [52][53][54] These 2 pathways may act synergistically to contribute to the observed human ILC boost in BRGSF HIS mice. NK cells engage in bidirectional interactions with other innate effectors that modulate their differentiation, homeostasis, and immune responses against pathogens and cancer.…”

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.…”