ULBP1, 2, 3: novel MHC class I-related molecules that bind to human cytomegalovirus glycoprotein UL16, activate NK cells

Kubin, Marek; Cassiano, Linda; Chalupny, Jan; Chin, Wilson; Cosman, David; Fanslow, William C.; Mullberg, Jürgen; Rousseau, Anne-Marie; Ulrich, Dawn; Armitage, Richard J.

doi:10.1002/1521-4141(200105)31:5<1428::aid-immu1428>3.0.co;2-4

Cited by 136 publications

(93 citation statements)

References 34 publications

(30 reference statements)

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“…The findings appear inconsistent with the report that ULBP3 binds to NKG2D and activates NK cells as well as other ULBPs. 42,47 As another feature, only ULBP3 was exclusively expressed on the membrane of CD34 ϩ BM cells of healthy donors. In addition, ULBP3 has been reported to not bind to CMV-UL16 in contrast to other ULBPs.…”

Section: Discussionmentioning

confidence: 99%

“…44 Once the stressinducible proteins emerge on the cell surface, cytotoxic cells such as NK cells and CTLs catch the molecules using their activating receptor NKG2D and eliminate the cells exposed to stress. 42,47,48 Both ULBP and MICA/B share NKG2D as a receptor. 42,48 The receptor is present on human NK and T cells (CD8 ϩ T, ␥␦ T, and a part of CD4 ϩ T cells).…”

Section: Introductionmentioning

confidence: 99%

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Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

Hanaoka

Kawaguchi

Horikawa

et al. 2006

Blood

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The mechanism by which paroxysmal nocturnal hemoglobinuria (PNH) clones expand is unknown. PNH clones harbor PIGA mutations and do not synthesize glycosylphosphatidylinositol (GPI), resulting in deficiency of GPI-linked membrane proteins. GPI-deficient blood cells often expand in patients with aplastic anemia who sustain immune-mediated marrow injury putatively induced by cytotoxic cells, hence suggesting that the injury allows PNH clones to expand selectively. We previously reported that leukemic K562 cells preferentially survived natural killer (NK) cell-mediated cytotoxicity in vitro when they acquired PIGA mutations. We herein show that the survival is ascribable to the deficiency of stress-inducible GPI-linked membrane proteins ULBP1 and ULBP2, which activate NK and T cells. The ULBPs were detected on GPI-expressing but not on GPI-deficient K562 cells. IntroductionParoxysmal nocturnal hemoglobinuria (PNH) is an acquired stem cell disorder of clonal nature characterized by intravascular hemolysis, venous thrombosis, bone marrow (BM) dysfunction, and infrequent development of leukemia. [1][2][3][4] In the last 2 decades, virtually the entire mechanism leading to PNH hemolysis has been elucidated. [5][6][7][8] PNH stem cells acquire PIGA mutations and do not generate glycosylphosphatidylinositol (GPI), resulting in a deficiency of a series of GPI-linked membrane proteins, including complement regulatory molecules such as decay-accelerating factor (DAF) and CD59. PNH cells are then vulnerable to autologous complement. For example, PNH erythrocytes undergo complement-mediated hemolysis. Soon after, the molecular events leading to clinically serious hemolytic precipitation induced by infection were clarified. 9 On the other hand, more than half of patients with PNH show various cytopenias and decreased CD34 ϩ hematopoietic cells. [1][2][3][4][10][11][12] PNH closely associates with aplastic anemia and myelodysplastic syndromes (MDSs) that share BM failure and development of leukemia. 1,12,13 It has been indicated that immune-mediated BM injury underlies at least a part of the diseases. 1,12 Indeed, immunosuppressive therapy ameliorates their marrow failure. 1,12,14,15 Of interest, combination therapy with antithymocyte globulin and cyclosporine A, these immunosuppressants having individual target spectra, 16,17 gives better results than therapy with each 1 of the 2 immunosuppressants. 12,18 In general, both cytotoxic T lymphocytes (CTLs) of adaptive immunity and natural killer (NK) cells of innate immunity operate in combination rather than independently. [19][20][21][22] It is then conceivable that both cytotoxic cells exert critical roles in BM injury, 12,[23][24][25][26] although real features of the autoimmunity have not been delineated.The marked progress in understanding of PNH pathophysiology evokes the next concern about the etiology of PNH, and the mechanisms of both selective expansion of PNH clones 27 and development of leukemia. 28 Above all, we have focused on the expansion of affected cells to mani...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

Hanaoka

Kawaguchi

Horikawa

et al. 2006

Blood

View full text Add to dashboard Cite

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“…Reverse transcription-PCR carried out to phenotype the expression of other NKG2 receptor family members revealed relatively high levels of mRNAs for NKG2A and NKG2D, a lower level for NKG2F, NKG2H, and DAP12, but no NKG2C and E mRNAs (data not shown). An inhibitory role for soluble HCMV gpUL16 has been suggested, because it binds MIC B and ULBPs (32,33) and therefore could block binding between MIC B and its activating receptor NKG2D͞DAP10 (34). Both the UL18 and UL16 genes are present in HCMV strain AD169 and ⌬UL40; however, neither of these potentially inhibitory HCMV genes were dominant over UL40 in our assays.…”

Section: Discussionmentioning

confidence: 99%

UL40-mediated NK evasion during productive infection with human cytomegalovirus

Wang

McSharry

Retière

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

150

126

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Human cytomegalovirus (HCMV) exploits a range of strategies to evade and modulate the immune response. Its capacity to downregulate MHC I expression was anticipated to render infected cells vulnerable to natural killer (NK) attack. Kinetic analysis revealed that during productive infection, HCMV strain AD169 first enhanced and then inhibited lysis of primary skin fibroblasts by a CD94͞NKG2A ؉ NKG2D ؉ ILT2 ؉ NK line. The inhibition of cytotoxicity against strain AD169-infected fibroblasts was abolished by prior treatment of targets or effectors with anti-MHC I and anti-CD94 monoclonal antibodies, respectively, implying a CD94͞HLA-Edependent mechanism. An HCMV strain AD169, UL40 deletion mutant could not inhibit CD94͞NKG2A ؉ NK killing against skin fibroblasts. The contribution of UL40 to evasion of primary NK cells then was tested in a system where targets and effectors were MHC-matched. Primary NK cells activated with IFN␣ as well as cultured primary NK cell lines showed increased killing against ⌬UL40-infected fibroblasts compared with AD169-infected targets. This effect was abrogated by depletion of CD94 ؉ cells. These findings demonstrate that HCMV encodes a mechanism of evasion specifically targeted against a proportion of CD94 ؉ NK cells and show that this system functions during a productive infection. NK cells ͉ inhibitionH uman cytomegalovirus (HCMV) is the prototypical ␤-herpesvirus and an important pathogen, being the major viral cause of congenital malformation and associated with severe morbidity in immunocompromised individuals. Primary infection is followed by lifelong persistence. The cellular immune response is crucial in controlling infection and providing resistance to disease (1). HCMV encodes an impressive arsenal of genes that act to counter MHC I-restricted cytotoxic T lymphocyte recognition by down-regulation of MHC I at various stages of the replicative cycle (reviewed in ref.2).Although down-regulation of MHC I expression is associated with protection against antigen-specific cytotoxic T lymphocytes, it also may enhance natural killer (NK) recognition of HCMVinfected cells. The importance of NK cells for control of CMV has been shown in vivo: in mice, an NK resistance locus, cmv1, has been identified (3) and mapped to the gene for Ly-49H, an NK-activating receptor (4, 5); in humans, an absence of NK cells increases susceptibility to several herpesvirus infections including HCMV (6). A number of human NK-activating and -inhibitory receptors have now been identified (reviewed in refs. 7-9). Members of the killer inhibitory receptor (KIR) family and the leukocyte Ig-like receptors (LIR-1͞ILT-2 and LIR-2͞ILT-4) bind HLA class I molecules. The HCMV MHC I homolog gpUL18 exhibits high affinity for LIR-1͞ILT-2 (10, 11); however, the function of gpUL18 during virus infection is yet to be resolved. A surface C-type lectin receptor CD94͞NKG2A͞B also has been shown to interact specifically with the nonclassical MHC I molecule, HLA-E, to deliver an inhibitory signal to NK cells (12)(13)(14). HLA-E ex...

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“…MIC proteins can be induced by ''heat shock'' of epithelial cell lines (19). Recently, Cosman and colleagues (20,21) identified another family of ligands for human NKG2D, designated the UL binding proteins (ULBP)-1, -2, and -3 molecules. Although similar to class I MHC molecules in their ␣1 and ␣2 domains, the genes encoding these proteins are not localized within the MHC.…”

mentioning

confidence: 99%

Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumorin vivo

Cerwenka

Baron

Lanier

2001

Proc. Natl. Acad. Sci. U.S.A.

536

455

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ULBP1, 2, 3: novel MHC class I-related molecules that bind to human cytomegalovirus glycoprotein UL16, activate NK cells

Cited by 136 publications

References 34 publications

Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

UL40-mediated NK evasion during productive infection with human cytomegalovirus

Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumorin vivo

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