Surface CD107a/LAMP-1 protects natural killer cells from degranulation-associated damage

Cohnen, André; Chiang, Samuel C.C.; Stojanović, Ana; Schmidt, Hannelore; Claus, Maren; Säftig, Paul; Janßen, Ottmar; Cerwenka, Adelheid; Bryceson, Yenan T.; Watzl, Carsten

doi:10.1182/blood-2012-07-441832

Cited by 118 publications

(102 citation statements)

References 44 publications

(57 reference statements)

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“…Moreover, CD107a plays an important role in the survival of NK cells against degranulation. 32 We observed the increased expression of this CD107a on the surface of CD56 1 NK cells at 24 h post-stimulation with MMF, and this activity was closely associated with the effects of MMF on degranulation and the release of Granzyme B from CD56 1 cells, likely reflecting the ability of this drug to induce the killing of K562 and RAJI cells through CD56 1 NK cells.…”

Section: Discussionmentioning

confidence: 81%

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

et al. 2014

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Dimethyl fumarate (DMF) is a new drug used to treat multiple sclerosis (MS) patients. Here, we examined the effects of DMF and the DMF metabolite monomethyl fumarate (MMF) on various activities of natural killer (NK) cells. We demonstrated that MMF augments the primary CD56 1 , but not CD56 2 , NK cell lysis of K562 and RAJI tumor cells. MMF induced NKp46 expression on the surface of CD56 1 , but not CD56 2 , NK cells after incubation for 24 h. This effect was closely correlated with the upregulation of CD107a expression on the surface of CD56 1 NK cells and the induction of Granzyme B release from these cells through this metabolite. An anti-NKp46 antibody inhibited the MMF-induced upregulation of CD107a and the lysis of tumor cells through CD56 1 NK cells. Thus, these results are the first to show that MMF augments CD56 1 NK cell lysis of tumor target cells, an effect mediated through NKp46. This novel effect suggests the use of MMF for therapeutic and/or preventive protocols in cancer.

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Section: Discussionmentioning

confidence: 81%

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

et al. 2014

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“…This would be consistent with a recently proposed novel role of CD107a, since engineered surface expression of CD107a has recently been shown to protect NK cells from degranulation-associated damage. 67 Our current work emphasizes the potential of the mevalonate pathway as an important therapeutic target as it provides multiple potent danger signals for human Vg9Vd2 T cells (Fig. 8).…”

Section: E953410-6mentioning

confidence: 73%

Stress-related and homeostatic cytokines regulate Vγ9Vδ2 T-cell surveillance of mevalonate metabolism

et al. 2014

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The potentially oncogenic mevalonate pathway provides building blocks for protein prenylation and induces cell proliferation and as such is an important therapeutic target. Among mevalonate metabolites, only isopentenyl pyrophosphate (IPP) has been considered to be an immunologically relevant antigen for primate-specific, innate-like Vg9Vd2 T cells with antitumor potential. We show here that Vg9Vd2 T cells pretreated with the stress-related, inflammasome-dependent cytokine interleukin 18 (IL-18) were potently activated not only by IPP but also by all downstream isoprenoid pyrophosphates that exhibit combined features of antigens and cell-extrinsic metabolic cues. Vg9Vd2 T cells induced this way effectively proliferated even under severe lymphopenic conditions and the antioxidant N-acetylcysteine significantly improved reconstitution of gd T cells predominantly with a central memory phenotype. The homeostatic cytokine IL-15 induced the differentiation of effector cells in an antigen-independent fashion, which rapidly produced abundant interferon g (IFNg) upon antigen re-encounter. IL-15 induced effector gd T cells displayed increased levels of the cytotoxic lymphocyte-associated proteins CD56, CD96, CD161 and perforin. In response to stimulation with isoprenoid pyrophosphates, these effector cells upregulated surface expression of CD107a and exhibited strong cytotoxicity against tumor cells in vitro. Our data clarify understanding of innate immunosurveillance mechanisms and will facilitate the controlled generation of robust Vg9Vd2 T cell subsets for effective cancer immunotherapy.

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“…35 Such protection is partly achieved by a balanced interaction between CD158 (KIR2D) on dNK cells and HLA-C on trophoblast cells. 13 Additionally, because CD107a reactivity may protect peripheral NK cells from degranulation-associated damage, 36 we suggest that dNK may similarly adopt this strategy to limit self-destruction and to maintain their presence and angiogenic capability at the maternal-fetal interface. Furthermore, we demonstrated that the maintenance of dNK function (IFN-c/ CD107a expression) was dependent upon cellular interactions between dNK cells and HTR-8 trophoblast cells (irrespective of the presence of activating receptors NKG2D or NKp80).…”

Section: Discussionmentioning

confidence: 96%

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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Surface CD107a/LAMP-1 protects natural killer cells from degranulation-associated damage

Abstract: Key Points CD107a protects cytotoxic lymphocytes from damage during degranulation. Interference with CD107a expression can cause the death of cytotoxic lymphocytes during degranulation.

Cited by 118 publications

References 44 publications

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

Stress-related and homeostatic cytokines regulate Vγ9Vδ2 T-cell surveillance of mevalonate metabolism

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

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