Expression and function of KIR and natural cytotoxicity receptors in NK-type lymphoproliferative diseases of granular lymphocytes

Zambello, Renato; Falco, Michela; Chiesa, Mariella Della; Trentin, Livio; Carollo, Davide; Castriconi, Roberta; Cannas, Giovanna; Carlomagno, Simona; Cabrelle, Anna; Lamy, Thierry; Agostini, Carlo; Moretta, Alessandro; Semenzato, Gianpietro; Vitale, Massimo

doi:10.1182/blood-2002-12-3898

Cited by 104 publications

(88 citation statements)

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“…33 In addition, patients with large granular lymphocyte (LGL) leukemia, which shares pathogenetic overlap with bone marrow failure syndromes such as aplastic anemia and MDS, have reduction in both NKp30 and NKp46 expression and reduced NCR function. 34 Similar to our findings, NCR expression in patients with LGL leukemia was restored by IL-2. 34 Therefore, the reduced NKp30 expression in both MDS and LGL leukemia represents a biologic feature common to these syndromes.…”

Section: Natural Killer Function In Mds Patients 4821supporting

confidence: 80%

Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors

Epling-Burnette

Bai

Painter

et al. 2007

Blood

198

171

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Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis with potential for progression to acute myeloid leukemia (AML). We compared natural killer (NK) cytolytic function in 48 MDS patients with 37 healthy donors and found reduced activity in the patient population (K562 cytolysis, 19% ؎ 21% SD versus 40% ؎ 17%) (P < .001). NK cytotoxicity in MDS patients was reduced against 3 disparate tumor targets with differential activating receptor requirement, suggesting global defects in NK function. Reduced NK function in MDS was significantly associated with higher International Prognostic Score (P ‫؍‬ .01), abnormal karyotype (P ‫؍‬ .05), the presence of excess blasts (P ‫؍‬ .01), and ageadjusted bone marrow hypercellularity (P ‫؍‬ .04). MDS patients had a display of the activating receptor NKp30, and NKG2D down-regulation closely correlated with impaired NK function (P ‫؍‬ . IntroductionThe myelodysplastic syndromes (MDS) are stem cell malignancies that display hematologic heterogeneity but share features of ineffective hematopoiesis and a potential for progression to acute myeloid leukemia (AML). 1,2 Multiple factors have been implicated in the pathogenesis of MDS, including cytogenetic and molecular abnormalities and disturbance in cellular immunity. Abnormal natural killer (NK) function, including reduced antibody-dependent cell cytotoxicity (ADCC) and diminished direct NK cell cytolytic function, have been previously described; however, the biologic mechanisms underlying these changes have not be defined. [3][4][5][6][7] Normal NK cells, ␥␦ T cells, and some ␣␤ T cells mediate their biologic action through 3 families of NK receptors: killer cell immunoglobulin-like receptors (KIRs), C lectin-like (NKG2) family receptors, and natural cytotoxicity receptors ([NCRs] eg, NKp30, NKp44, and NKp46). 8 Regulation of innate immunity occurs through balanced signaling by these families of NK receptors with activating and inhibitory function. [9][10][11] Constitutively expressed activating receptors such as NKp46 and NKp30 along with NKG2D mediate most non-major histocompatibility complex (non-MHC)-induced tumor-specific cytotoxicity by NK cells, and the activation-restricted NCR (NKp44) increases NK cytotoxicity after cytokine activation. 12 Although many NK receptors with both activating and inhibitory function have been identified and details of their downstream signaling pathways have been elucidated, a void exists in the identification of activatory NK ligands and the pathologic situations in which they are induced in tumor and virally infected cells. The best-characterized NK receptor ligands are the stress-inducible MHC class I-related chain A (MICA), MICB, and UL16-binding proteins (ULBPs), which constitute the major cellular ligands for human NKG2D. [13][14][15][16][17] In addition to viralinduced expression, NKG2D ligands are often expressed by tumor cells. 18,19 Ligands for NKp30, NKp44, and NKp46 have not yet been delineated.In MDS, the pathogenesis and clinical implications of reduced NK ...

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Section: Natural Killer Function In Mds Patients 4821supporting

confidence: 80%

Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors

Epling-Burnette

Bai

Painter

et al. 2007

Blood

198

171

View full text Add to dashboard Cite

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“…Moreover, low NCR surface density on NK cells of HIV-1-infected individuals and AML patients was associated with the inability of NK cells to kill target cells [20,22]. NCR are also expressed at significantly low levels in NK cells from patients with NK cell expansions, suggesting that these receptors may not be involved in the expansion process [23].…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors

et al. 2004

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NKG2D and natural cytotoxicity receptors (NCR) are essential recognition structures that mediate NK cell activation. NKG2D and NCR signaling is achieved through membrane association with signaling adaptors. The adaptors that associate with NCR -such as CD3´, FcR + and KARAP/DAP12 -bear intracytoplasmic immunoreceptor tyrosine-based activation motifs that activate Syk protein tyrosine kinases. Human NKG2D associates with the DAP10 transmembrane adaptor, which bears a YxxM motif and activates the phosphatidylinositol 3-kinase pathway. In the mouse, a short NKG2D-S isoform, generated by Nkg2d alternative splicing, can associate with either DAP10 or KARAP/DAP12. Here, we report that neither short human NKG2D alternative transcripts nor NKG2D association with KARAP/ DAP12 was detected in activated human NK cells. Despite these results, NK cell triggering by both recombinant soluble NKG2D ligands (MICA and ULBP-1) and anti-NCR crosslinking antibodies induced similar CD25 expression, NK cell proliferation and cytokine production. In contrast, NKG2D triggering by anti-NKG2D antibodies did not lead to any detectable activation signals. These data thus show that target recognition via NKG2D or NCR triggers all aspects of NK activation, and pave the way for further dissection of the signaling pathways induced by NK cell recognition of ULBP-1 and MICA. The first three authors contributed equally to this work. Abbreviations: CFSE:Carboxyfluoresceine diacetate succinimidyl ester ITAM: Immunoreceptor tyrosine-based activation motif NCR: Natural cytotoxicity receptor RLM 5'-RACE: RNA-ligase-mediated rapid amplification of cDNA ends

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“…This feature is intrinsically nested in a genetic background, which determines a biased response of NK cells sustained by cells equipped with activating NK receptors. In fact, a typical feature of patients with CLPD-NK is preferential expression of the activating isoforms of killer immunoglobin-like receptors (KIR) [25][26][27] and this pattern correlates with reduced expression of other activating receptors, 25 such as natural cytotoxicity receptors. Together with a bias towards activating KIR expression, marked silencing of inhibitory KIR through increased gene methylation has been reported (Gattazzo et al, unpublished data) and a similar epigenetic mechanism has been proposed for TSC-22 gene expression silencing.…”

mentioning

confidence: 99%

Large granular lymphocyte disorders: new etiopathogenetic clues as a rationale for innovative therapeutic approaches

Zambello¹,

Semenzato²

2009

Haematologica

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F e r r a t a S t o r t i F o u n d a t i o nhaplotype with a higher frequency than the normal population, as occurs in patients with rheumatoid arthritis. In recent years progress has been made in understanding the mechanisms sustaining T-LGL leukemia and CLPD-NK. It is now becoming evident that the phenotype of T-cell LGL leukemia is consistent with that of fully differentiated cytotoxic T lymphocytes. The hallmark of T-LGL leukemia lymphocytes is the failure to undergo activation-induced cell death (AICD), this event being consequent to a critical impairment of apoptotic pathways. T-LGL leukemia is characterized by an abnormal clonal expansion of antigen-primed mature cytotoxic T-lymphocytes (CTL) which successfully escape AICD and remain competent in the long-term. 10 Clearance of potentially harmful antigen-stimulated effector cytotoxic T-cells after a successful immune response occurs physiologically by triggering Fas-mediated apoptosis through induction of a death-inducing signaling complex (DISC). This process, which is crucial to T-cell homeostasis, requires fine tuning between proliferation, survival, and apoptosis. Like normal activated CTL, leukemic T-LGL cells exhibit activation of multiple survival signaling pathways. 6 However, unlike normal activated CTL, leukemic T-LGL cells are not sensitive to Fas-induced apoptosis, 20 a process that is essential for AICD. 21 Fas resistance can occur in cells with overexpression of the DISC inhibitory protein c-FLIP. This latter is constitutively expressed in leukemic LGL and prevents DISC formation and Fas-mediated apoptosis. 22 Several genes are likely to be involved in the above mentioned processes and gene expression profiling has revealed that leukemic LGL are characterized by the expression of genes affecting apoptosis, regulation of TCR signaling and immune response. 23 This supports the view that an uncoupling of activation and apoptotic pathways is responsible for the failure of AICD. In fact, genes that are up-regulated in leukemic LGL have antiapoptotic functions whereas those that are down-regulated are pro-apoptotic. Pathway-based microarray analysis also indicated that the balance of pro-apoptotic (ceramide and its analogs) and anti-apoptotic (sphingosine-1-phosphate, S1P) sphingolipid-mediated signaling is deregulated in leukemic LGL in favor of S1P. 23 Of great interest is the model suggesting that the persistence of interleukin-15 and platelet-derived growth factor is sufficient to reproduce all known deregulations in leukemic T-LGL. 10 Interleukin-15 alters expression of Bcl-2 family members, i.e. Bcl-2, Bcl-XL, Bim, Noxa, and Mcl-1. Genes belonging to the BCL-2 family, such as the BCL-2 related X gene (BAX) are down-regulated, while the myeloid cell factor (MCL-1) is up-regulated. In primary leukemic LGL, Bid (which is down-regulated by interleukin-15) levels are low but are reversed following bortezomib treatment, with subsequent increases in LGL apoptosis. These data provide a novel molecular mechanism for interleukin-15 control of Bid whi...

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Expression and function of KIR and natural cytotoxicity receptors in NK-type lymphoproliferative diseases of granular lymphocytes

Cited by 104 publications

References 54 publications

Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors

Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors

Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors

Large granular lymphocyte disorders: new etiopathogenetic clues as a rationale for innovative therapeutic approaches

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