Engagement of ILT2/CD85j in Sézary syndrome cells inhibits their CD3/TCR signaling

Nikolova, Maria; Musette, Philippe; Bagot, M.; Boumsell, Laurence; Bensussan, Armand

doi:10.1182/blood-2001-12-0303

Cited by 30 publications

(22 citation statements)

References 42 publications

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“…Further downstream of the TCR, we identified a loss of PLCg-1 activation that leads to reduced ROS production and abrogated intracellular Ca 2+ release specifically in CTCL cells. In line with our findings, Nikolova and colleagues (28) suggested that the reduction of TCR signaling by inhibitory receptors (CD158k/KIT3DL2 and CD85j/ILT-2R) may lead to AICD resistance as seen in ILT-2R-expressing T cells. The finding of reduced TCR signaling in CTCL cells was also reported by Fargnoli and colleagues (29) who showed decreased activities of Zap70, Syk and membraneassociated Csk after TCR stimulation.…”

Section: Discussionsupporting

confidence: 79%

Lack of T-Cell Receptor–Induced Signaling Is Crucial for CD95 Ligand Up-regulation and Protects Cutaneous T-Cell Lymphoma Cells from Activation-Induced Cell Death

et al. 2009

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Restimulation of previously activated T cells via the T-cell receptor (TCR) leads to activation-induced cell death (AICD), which is, at least in part, dependent on the death receptor CD95 (APO-1, FAS) and its natural ligand (CD95L). Here, we characterize cutaneous T-cell lymphoma (CTCL) cells (CTCL tumor cell lines and primary CTCL tumor cells from CTCL patients) as AICD resistant. We show that CTCL cells have elevated levels of the CD95-inhibitory protein cFLIP. However, cFLIP is not responsible for CTCL AICD resistance. Instead, our data suggest that reduced TCR-proximal signaling in CTCL cells is responsible for the observed AICD resistance. CTCL cells exhibit no PLC-;1 activity, resulting in an impaired Ca 2+ release and reduced generation of reactive oxygen species upon TCR stimulation. Ca 2+ and ROS production are crucial for up-regulation of CD95L and reconstitution of both signals resulted in AICD sensitivity of CTCL cells. In accordance with these data, CTCL tumor cells from patients with Sézary syndrome do not up-regulate CD95L upon TCR-stimulation and are therefore resistant to AICD. These results show a novel mechanism of AICD resistance in CTCL that could have future therapeutic implications to overcome apoptosis resistance in CTCL patients. [Cancer Res 2009;69(10):4175-83]

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Section: Discussionsupporting

confidence: 79%

Lack of T-Cell Receptor–Induced Signaling Is Crucial for CD95 Ligand Up-regulation and Protects Cutaneous T-Cell Lymphoma Cells from Activation-Induced Cell Death

et al. 2009

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“…It is detected on the surface of a proportion of T cells (19,20) and in the cytoplasm of all T lymphocytes (21). Cytoplasmic expression of CD85j in all CD4 ϩ T cells has been recently confirmed (22). CD85j is functional in all T cells, independently of its surface expression (21), and it down-regulates Ag-specific functions of T lymphocytes (21,23).…”

mentioning

confidence: 96%

Specific Recognition of the Viral Protein UL18 by CD85j/LIR-1/ILT2 on CD8+ T Cells Mediates the Non-MHC-Restricted Lysis of Human Cytomegalovirus-Infected Cells

Saverino¹,

Ghiotto²,

Merlo³

et al. 2004

The Journal of Immunology

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Immune evasion mechanisms of human CMV are known; however, the immune control of infection remains poorly elucidated. We show that interaction between the viral protein UL18 on infected cells and the invariant receptor CD85j/LIR-1/ILT2 expressed on CTL is relevant for the control of infection. Resting and activated CD8+ T cells lysed UL18 expressing cells, whereas cells infected with CMV defective for UL18 were not killed. Lysis was not dependent on CD8+ T cell Ag specificity, MHC-unrestricted and specifically blocked by anti-CD85j and anti-UL18 mAb. Moreover, soluble recombinant UL18Fc immunoprecipitated CD85j from T cells. Activation is mediated by CD85j and its pathway is unrelated to CD3/TCR engagement. UL18 is detected in immunocompromised patients with productive infection and the mechanism used in vivo by human CMV to ensure survival of the immunocompetent host may be mediated by activation signals delivered by infected cells to T lymphocytes via UL18/CD85j interactions.

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“…ILT2 triggering induces phosphorylation of intra-cytoplasmic ITIMs, which become docking sites for the SHP-1 and SHP-2 phosphatases [16,17]. Once recruited to the NK/tumor cell interface, the SHP-1 and SHP-2 phosphatases disable activatory signal transduction pathways through the dephosphorylation of signaling components, ultimately leading to inhibition of NK-cell activation.…”

Section: Introductionmentioning

confidence: 99%

HLA‐G inhibition of NK‐cell cytolytic function is uncoupled from tumor cell lipid raft reorganization

Baudhuin¹,

Lesport²,

Sousa³

et al. 2012

Eur J Immunol

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HLA-G is a non-classical HLA class I molecule with tolerogenic properties and restricted tissue distribution. The expression of HLA-G can be induced by tumors thus providing an efficient way to escape the anti-tumoral immune response. Although lipid rafts regulate diverse immunological mechanisms their relationship with HLA-G remains controversial. Our results show that HLA-G-mediated inhibition of both the interaction between NK and tumor cells, and of intracellular calcium flux in NK cells conjugated to their target cells were independent of lipid raft integrity. In addition, cytotoxicity assays indicated that HLA-G continued to efficiently inhibit NK-cell cytolytic function in several different tumor cells independently of lipid raft integrity. Confocal microscopy with 3D reconstruction combined with biochemical analysis showed that HLA-G was mainly localized outside the lipid rafts of tumor cells after cross-linking with specific antibody and remained excluded from lipid rafts during interaction with the ILT2 inhibitory receptor of NK cells. This study indicates that the inhibitory function of HLA-G is uncoupled from lipid raft organization, further distinguishing HLA-G from classical HLA molecules and providing novel information in the understanding of tumor immune escape mechanism mediated through HLA-G.

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Engagement of ILT2/CD85j in Sézary syndrome cells inhibits their CD3/TCR signaling

Cited by 30 publications

References 42 publications

Lack of T-Cell Receptor–Induced Signaling Is Crucial for CD95 Ligand Up-regulation and Protects Cutaneous T-Cell Lymphoma Cells from Activation-Induced Cell Death

Lack of T-Cell Receptor–Induced Signaling Is Crucial for CD95 Ligand Up-regulation and Protects Cutaneous T-Cell Lymphoma Cells from Activation-Induced Cell Death

Specific Recognition of the Viral Protein UL18 by CD85j/LIR-1/ILT2 on CD8+ T Cells Mediates the Non-MHC-Restricted Lysis of Human Cytomegalovirus-Infected Cells

HLA‐G inhibition of NK‐cell cytolytic function is uncoupled from tumor cell lipid raft reorganization

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