NKp80 Defines a Critical Step during Human Natural Killer Cell Development

Abstract

SUMMARY Human natural killer (NK) cells develop in secondary lymphoid tissues (SLTs) through distinct stages. We identified two SLT lineage (Lin)−CD34−CD117+/−CD94+CD16− “stage 4” subsets according to expression of the C-type lectin-like surface activating receptor, NKp80: NKp80− (stage “4a”) and NKp80+ (stage “4b”). Whereas stage 4b cells expressed more of the transcription factors T-BET and EOMES, produced interferon-gamma, and were cytotoxic, stage 4a cells expressed more of the transcription factors RORγt and AHR and produced interleukin-22, similar to SLT Lin−CD34−CD117+CD94−CD16− “stage 3” cells whose phenotype overlaps with that of Group 3 innate lymphoid cells (ILC3s). Co-culture with dendritic cells or transplantation into immunodeficient mice produced mature NK cells from stage 3 and stage 4a populations. These data identify NKp80 as a marker of NK cell maturity in SLTs and support a model of human NK cell development through a stage 4a intermediate with ILC3-associated features.

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

“…33 However, we demonstrate that human NKp44 1 bona fide ILC3s from secondary lymphoid tissues can develop into functional equivalents of NK cells, and this developmental pathway, which demonstrates many similarities to NK-cell differentiation from stage 3 precursors, 17,18 might provide cytotoxic protection at mucosal barriers.…”

“…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).…”

“…[13][14][15] NK cells do not develop exclusively in the bone marrow and seem to undergo functional maturation in the periphery. 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.…”

“…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.…”

HemITAM: A single tyrosine motif that packs a punch

“…An NK-monocyte cross-talk leads to mutual activation of NK and myeloid cells, resulting in cytokine production (78), whereas AICL-positive NK cells are rendered susceptible to cytotoxicity through bystander NK cells, which are in turn activated to produce cytokines (79). Further, NKp80 has been identified as a marker for mature cytotoxic, perforin-expressing NK cells in NK cell development (80).…”