Genetically coupled receptor–ligand pair NKp80-AICL enables autonomous control of human NK cell responses

Klimosch, Sascha N.; Bartel, Yvonne; Wiemann, Stefan; Steinle, Alexander

doi:10.1182/blood-2013-01-479790

Cited by 39 publications

(48 citation statements)

References 38 publications

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“…Moreover, either blockade or upregulation of NKG2D/NKp80 has no significant effect on IFN-c or CD107a expression by dNK cells, indicating that they are not sufficient on their own to induce dNK cell immune responses (JH Zhang and SJ Lye et al, unpublished data). Thus our data are consistent with other reports on peripheral NK cells 33,34 and suggest that in vivo dNK cytotoxicity and pro-inflammatory reactivity are controlled by multiple receptor-ligand interactions.…”

Section: Discussionsupporting

confidence: 95%

Human dNK cell function is differentially regulated by extrinsic cellular engagement and intrinsic activating receptors in first and second trimester pregnancy

et al. 2015

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Decidual natural killer (dNK) cells express an array of activation receptors to regulate placental immunity and development during early pregnancy. We investigated the functional character of human dNK cells during the first and second trimester of gestation and the interaction between dNK and trophoblast cells. Although the frequency of CD56CD16 dNK among the total CD45 leukocytes did not change over this period, the expression of the activating receptors, NKp80 and NKG2D, was greatly upregulated. We observed a significantly higher number of extravillous trophoblast cells in proximity to the dNK cells in the first trimester in comparison with the second trimester decidua. NKG2D expression by first trimester dNK cells was decreased when co-cultured with the HTR-8 trophoblast cell line. In the second trimester, functional markers of dNK activation, i.e., angiogenic factor production (e.g., vascular endothelial growth factor, interleukin-8, interferon-gamma), remained stable despite an increase in NKp80 or NKG2D surface expression. Furthermore, the degranulation capacity of dNK cells, as assessed by CD107a, was decreased in the second trimester. We suggest that in the first trimester, trophoblast-dNK interactions generate a population of dNK cells with a suppressed activating phenotype. In the second trimester, the loss of trophoblast-dNK interactions led to the inhibition of dNK cell function, although their activating receptor expression was increased. We speculate that during pregnancy, two mechanisms operate to modulate the dNK cell activation:suppression of activating receptor levels in the first trimester by trophoblasts and disengagement of receptor-ligand coupling in the second trimester.

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Section: Discussionsupporting

confidence: 95%

Human dNK cell function is differentially regulated by extrinsic cellular engagement and intrinsic activating receptors in first and second trimester pregnancy

et al. 2015

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“…Moreover, NKp80 expression was significantly downregulated on stage 4b and stage 5 cells following in vitro co-culture with DCs (Figure 6G), similar to what occurs when PB NK cells are stimulated ex vivo (Klimosch et al, 2013). Therefore, while NKp80 expression correlated with NK cell functional maturity among ex vivo tested SLT ILCs, NKp80 expression did not correlate with NK cell differentiation following culture of stage 3 or stage 4a cells with DCs under the in vitro conditions tested here.…”

Section: Resultssupporting

confidence: 59%

NKp80 Defines a Critical Step during Human Natural Killer Cell Development

et al. 2016

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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.

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“…This was further supported by the increases in CD107a, HLA-DR, and CD69 expression. The decrease in NKp80 was reported recently to be associated with NK cell activation (27). In addition, expression of various KIRs in human NK cells in hu-HSC NOG-IL-2 Tg mice represented strong evidence that they are mature NK cells.…”

Section: Discussionmentioning

confidence: 72%

Predominant Development of Mature and Functional Human NK Cells in a Novel Human IL-2–Producing Transgenic NOG Mouse

Katano

Takahashi

Ito

et al. 2015

The Journal of Immunology

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We generated a severe immunodeficient NOD/Shi-scid-IL-2Rγnull (NOG) mouse substrain expressing the transgenic human IL-2 gene (NOG–IL-2 Tg). Upon transfer of human cord blood–derived hematopoietic stem cells (HSCs), CD3−CD56highCD16+/− cells developed unexpectedly, predominantly in the NOG–IL-2 Tg (hu-HSC NOG–IL-2 Tg). These cells expressed various NK receptors, including NKp30, NKp44, NKp46, NKG2D, and CD94, as well as a diverse set of killer cell Ig-like receptor molecules at levels comparable to normal human NK cells from the peripheral blood, which is evidence of their maturity. They produced levels of granzyme A as high as in human peripheral blood–derived NK cells, and a considerable amount of perforin protein was detected in the plasma. Human NK cells in hu-HSC NOG–IL-2 Tg produced IFN-γ upon stimulation, and IL-2, IL-15, or IL-12 treatment augmented the in vitro cytotoxicity. Inoculation of K562 leukemia cells into hu-HSC NOG–IL-2 Tg caused complete rejection of the tumor cells, whereas inoculation into hu-HSC NOG fully reconstituted with human B, T, and some NK cells did not. Moreover, when a CCR4+ Hodgkin’s lymphoma cell line was inoculated s.c. into hu-HSC NOG–IL-2 Tg, the tumor growth was significantly suppressed by treatment with a therapeutic humanized anti-CCR4 Ab (mogamulizumab), suggesting that the human NK cells in the mice exerted active Ab-dependent cellular cytotoxicity in vivo. Taken together, these data suggest that the new NOG–IL-2 Tg strain is a unique model that can be used to investigate the biological and pathological functions of human NK cells in vivo.

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Genetically coupled receptor–ligand pair NKp80-AICL enables autonomous control of human NK cell responses

Abstract: Key Points Human NK cells contain Golgi complex–associated intracellular stores of AICL, a ligand of the activating NK receptor NKp80. Upon exposure to inflammatory cytokines, AICL surfaces on NK cells, rendering them susceptible to NKp80-mediated bystander NK cytolysis.

Cited by 39 publications

References 38 publications

Human dNK cell function is differentially regulated by extrinsic cellular engagement and intrinsic activating receptors in first and second trimester pregnancy

Human dNK cell function is differentially regulated by extrinsic cellular engagement and intrinsic activating receptors in first and second trimester pregnancy

NKp80 Defines a Critical Step during Human Natural Killer Cell Development

Predominant Development of Mature and Functional Human NK Cells in a Novel Human IL-2–Producing Transgenic NOG Mouse

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