Soluble nonclassical HLA generated by the metalloproteinase pathway

Dong, Yuzhi; Lieskovská, Jaroslava; Kedrin, Dmitriy; Porcelli, Steven A.; Mandelboim, Ofer; Bushkin, Yuri

doi:10.1016/s0198-8859(03)00093-4

Cited by 52 publications

(41 citation statements)

References 46 publications

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“…2 Soluble HLA-G can also be generated by metalloproteinase-mediated release of surface HLA-G containing only extracellular domains. 3 The predominant expression of sHLA-G1 in the placenta, at a time when polymorphic HLA-A and HLA-B class Ia molecules are repressed, is consistent with important immunologic functions during pregnancy. 4 sHLA-G1 induces apoptosis of activated CD8 ϩ T and natural killer (NK) cells 5,6 and down-regulates the CD4 ϩ T-cell alloproliferation response.…”

mentioning

confidence: 79%

Soluble HLA-G1 inhibits angiogenesis through an apoptotic pathway and by direct binding to CD160 receptor expressed by endothelial cells

Fons

Chabot

Cartwright

et al. 2006

Blood

177

148

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HLA-G is a major histocompatibility complex class Ib molecule whose constitutive tissue distribution is restricted mainly to trophoblast cells at the maternal-fetal interface during pregnancy. In this study, we demonstrated the ability of the soluble HLA-G1 (sHLA-G1) isoform to inhibit fibroblast growth factor-2 (FGF2)-induced capillary-like tubule formation. Using a rabbit corneal neovascularization model, we further showed that sHLA-G1 inhibits FGF2-induced angiogenesis in vivo. We also demonstrated that sHLA-G1 induces endothelial cell apoptosis through binding to BY55/ CD160, a glycosylphosphatidylinositolanchored receptor expressed by endothelial cells. Furthermore, we showed that the specific CL1-R2 anti-CD160 monoclonal antibody mimics sHLA-G1-mediated inhibition of endothelial cell tube formation and induction of apoptosis. Thus, the engagement of CD160 in endothelial cells may be essential for the inhibition of angiogenesis. sHLA-G1/CD160-mediated antiangiogenic property may participate in the vascular remodeling of maternal spiral arteries during pregnancy, and, given that we found that CD160 is strongly expressed in the vasculature of a murine tumor, it offers an attractive therapeutic target for preventing pathologic neovascularization. ( IntroductionHLA-G is a human major histocompatibility complex (MHC) class Ib gene characterized by a unique promoter region, limited polymorphism, restricted constitutive tissue distribution, and several spliced transcripts encoding either membrane-bound or soluble proteins. 1 The soluble HLA-G1 (sHLA-G1) isoform derives from mRNA retaining intron 4, 2 which contains a stop codon that precludes translation of the transmembrane domain. Such intron 4 retention is unique among all HLA class I molecules described to date. This 37-kDa, intron 4-retaining sHLA-G1 isoform associates noncovalently with ␤2-microglobulin (␤2m). 2 Soluble HLA-G can also be generated by metalloproteinase-mediated release of surface HLA-G containing only extracellular domains. 3 The predominant expression of sHLA-G1 in the placenta, at a time when polymorphic HLA-A and HLA-B class Ia molecules are repressed, is consistent with important immunologic functions during pregnancy. 4 sHLA-G1 induces apoptosis of activated CD8 ϩ T and natural killer (NK) cells 5,6 and down-regulates the CD4 ϩ T-cell alloproliferation response. 7 The observation that some anti-HLA-G monoclonal antibodies bound to HLA-G-negative placental endothelial cells 8,9 led to our hypothesis that sHLA-G1 might bind to these cells and be involved in the modulation of placental angiogenesis or uterine vessel remodeling. 8 Several further observations are in line with such a novel function of HLA-G. Among them is that a defect of HLA-G expression in extravillous cytotrophoblast is associated with preeclampsia, 10,11 a common complication of pregnancy in which HLA-G ϩ endovascular trophoblast invasion of maternal spiral arteries is abrogated, compromising blood flow to the maternal interface. 12 In addition, it has been shown that HL...

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mentioning

confidence: 79%

Soluble HLA-G1 inhibits angiogenesis through an apoptotic pathway and by direct binding to CD160 receptor expressed by endothelial cells

Fons

Chabot

Cartwright

et al. 2006

Blood

177

148

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“…For example, the HLA-G FHC may bind the LIR-2 (ILT4) receptor similar to HLA-B27 FHC. One may assume a possible scenario in which the balance between the expression of MHC class I molecules (HLA-C, -E, and -G) present on EVT cells as FHC or as conformed proteins (24,58) would determine the strength of the inhibitory response. These FHCs following dissociation from ␤ 2 m are released from the cell surface through proteolytic cleavage by metalloproteases (24,58).…”

Section: Discussionmentioning

confidence: 99%

“…One may assume a possible scenario in which the balance between the expression of MHC class I molecules (HLA-C, -E, and -G) present on EVT cells as FHC or as conformed proteins (24,58) would determine the strength of the inhibitory response. These FHCs following dissociation from ␤ 2 m are released from the cell surface through proteolytic cleavage by metalloproteases (24,58). For example, in various pathological conditions, such as advanced HIV-1 infection or chronic hepatitis C, serum levels of ␤ 2 m-free HLA proteins are increased (59).…”

Section: Discussionmentioning

confidence: 99%

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The CD85J/Leukocyte Inhibitory Receptor-1 Distinguishes between Conformed and β2-Microglobulin-Free HLA-G Molecules

Gonen‐Gross¹,

Achdout²,

Arnon³

et al. 2005

The Journal of Immunology

Self Cite

106

121

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For a proper development of the placenta, maternal NK cells should not attack the fetal extravillous cytotrophoblast cells. This inhibition of maternal NK cells is partially mediated via the nonclassical MHC class I molecule HLA-G. Recently, we demonstrated that HLA-G forms disulfide-linked high molecular complexes on the surface of transfected cells. In the present study, we demonstrate that HLA-G must associate with β2m for its interaction with CD85J/leukocyte Ig-like receptor-1 (LIR-1). Although HLA-G free H chain complexes are expressed on the surface, they are not recognized and possibly interfere with CD85J/LIR-1 and HLA-G interaction. The formation of these complexes on the cell surface might represent a novel mechanism developed specifically by the HLA-G protein aimed to control the efficiency of the CD85J/LIR-1-mediated inhibition. We also show that endogenous HLA-G complexes are expressed on the cell surface. These findings provide novel insights into the delicate interaction between extravillous cytotrophoblast cells and NK cells in the decidua.

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“…We next investigated whether sHLA-E release by melanoma cells involved a proteolytic shedding, as described for classical (41) and for transfected nonclassical HLA class I molecules (42,43). The M200 cell line pretreated for 20 h with IFN-␥ was cultured for 4 h with chloroquine (lysosomal inhibitor), leupeptin (Ser/Thr proteinase inhibitor), PMSF (thiol proteinase inhibitor), EDTA (metalloproteinase inhibitor), or Galardin (broad spectrum matrix metalloproteinase (MMP) inhibitor) before HLA-E quantification in culture supernatant by Western blot.…”

Section: Melanocytes and Melanoma Cell Lines Produce A Soluble Form Omentioning

confidence: 99%

Expression and Release of HLA-E by Melanoma Cells and Melanocytes: Potential Impact on the Response of Cytotoxic Effector Cells

Derré

Corvaisier

Charreau

et al. 2006

The Journal of Immunology

135

118

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HLA-E are nonclassical MHC molecules with poorly characterized tissue distribution and functions. Because of their capacity to bind the inhibitory receptor, CD94/NKG2A, expressed by NK cells and CTL, HLA-E molecules might play an important role in immunomodulation. In particular, expression of HLA-E might favor tumor cell escape from CTL and NK immunosurveillance. To address the potential role of HLA-E in melanoma immunobiology, we assessed the expression of these molecules ex vivo in human melanoma biopsies and in melanoma and melanocyte cell lines. Melanoma cell lines expressed no or low surface, but significant intracellular levels of HLA-E. We also report for the first time that some of them produced a soluble form of this molecule. IFN-γ significantly increased the surface expression of HLA-E and the shedding of soluble HLA-E by these cells, in a metalloproteinase-dependent fashion. In contrast, melanocyte cell lines constitutively expressed HLA-E molecules that were detectable both at the cell surface and in the soluble form, at levels that were poorly affected by IFN-γ treatment. On tumor sections, a majority of tumor cells of primary, but a low proportion of metastatic melanomas (30–70 and 10–20%, respectively), expressed HLA-E. Finally, HLA-E expression at the cell surface of melanoma cells decreased their susceptibility to CTL lysis. These data demonstrate that HLA-E expression and shedding are normal features of melanocytes, which are conserved in melanoma cells of primary tumors, but become dependent on IFN-γ induction after metastasis. The biological significance of these findings warrants further investigation.

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Soluble nonclassical HLA generated by the metalloproteinase pathway

Cited by 52 publications

References 46 publications

Soluble HLA-G1 inhibits angiogenesis through an apoptotic pathway and by direct binding to CD160 receptor expressed by endothelial cells

Soluble HLA-G1 inhibits angiogenesis through an apoptotic pathway and by direct binding to CD160 receptor expressed by endothelial cells

The CD85J/Leukocyte Inhibitory Receptor-1 Distinguishes between Conformed and β2-Microglobulin-Free HLA-G Molecules

Expression and Release of HLA-E by Melanoma Cells and Melanocytes: Potential Impact on the Response of Cytotoxic Effector Cells

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