The role of SAP in murine CD150 (SLAM)-mediated T-cell proliferation and interferon γ production

Howie, Duncan; Okamoto, Susumo; Rietdijk, Svend; Clarke, Kareem; Wang, Ninghai; PhD, Charles A. Gullo; Bruggeman, Joost P.; Manning, Stephen; Coyle, Anthony J.; Greenfield, Edward; Kuchroo, Vijay K.; Terhorst, Cox

doi:10.1182/blood-2002-02-0445

Cited by 68 publications

(69 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although CD150-induced activation of Akt phosphorylation was observed in T and B lymphocytes 20,22 , UV-inactivated vaccine strain of MV was shown to inhibit IL-2 dependent activation of Akt pathway in T cells 33 . These disparities may be linked to differences in the cell types and viral strains, distinct mode of cell activation and finally surface interaction of lymphocytes with the MV glycoprotein complex independently of CD150.…”

Section: Discussionmentioning

confidence: 99%

“…As PI3K/ Akt pathway is one of the signaling pathways linked to CD150 engagement in lymphocytes 20,22 , we have assumed that MV may also trigger Akt in monocyte-derived human DCs. Our previous studies demonstrated that both infectious and UV-inactivated MV particles, in addition to the presence of viral envelope glycoproteins, contain an important quantity of free MV nucleoprotein, which can stimulate Fc receptor expressed on numerous cells, including DCs 34,35 .…”

Section: Mv-h Interaction With Cd150 Increases Akt Phosphorylation Inmentioning

confidence: 99%

“…The cytoplasmic tail of CD150 can bind the key SH2-containing components of signal transduction pathways, such as SHP-1, SHP-2, and SHIP, adaptor molecules SH2D1A/SAP and EAT-2, as well as Src-family kinases, including Fyn, FynT, Lyn, and Fgr, and also the p85 regulatory subunit of phosphatidylinositol-3 kinase [20][21][22] . CD150 was shown to regulate Akt (v-Akt murine thymoma viral oncogen)/PKB (protein kinase B) and MAPK (mitogen-activated protein kinase) signaling pathways in human B cells 23,24 and to induce Akt phosphorylation in CD4 1 T lymphocytes 20 . By binding to the CD150 cytoplasmic tail, the adaptor protein SH2D1A/SAP works as a molecular switch that regulates CD150-mediated signaling pathways 25 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

et al. 2015

View full text Add to dashboard Cite

Measles virus (MV) is highly contagious pathogen, which causes a profound immunosuppression, resulting in high infant mortality. This virus infects dendritic cells (DCs) following the binding of MV hemagglutinin (MV-H) to CD150 receptor and alters DC functions by a mechanism that is not completely understood. We have analyzed the effect of MV-H interaction with CD150-expressing DCs on the DC signaling pathways and consequent phenotypic and functional changes in the absence of infectious context. We demonstrated that contact between CD150 on human DCs and MV-H expressed on membrane of transfected CHO cells was sufficient to modulate the activity of two major regulatory pathways of DC differentiation and function: to stimulate Akt and inhibit p38 MAPK phosphorylation, without concomitant ERK1/2 activation. Furthermore, interaction with MV-H decreased the expression level of DC activation markers CD80, CD83, CD86, and HLA-DR and strongly downregulated IL-12 production but did not modulate IL-10 secretion. Moreover, contact with MV-H suppressed DC-mediated T-cell alloproliferation, demonstrating profound alteration of DC maturation and functions. Finally, engagement of CD150 by MV-H in mice transgenic for human CD150 decreased inflammatory responses, showing the immunosuppressive effect of CD150-MV-H interaction in vivo. Altogether, these results uncover novel mechanism of MV-induced immunosuppression, implicating modulation of cell signaling pathways following MV-H interaction with CD150-expressing DCs and reveal anti-inflammatory effects of CD150 stimulation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Mv-h Interaction With Cd150 Increases Akt Phosphorylation Inmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Given that macrophage functions in SLAM-deficient mice have previously been shown to be impaired (7), we cannot exclude the possibility that this cell type may contribute to the failure of SLAM-deficient mice to develop allergic responses. A recently described receptor for SLAM, termed SLAM-associated protein, has been identified (27). Whether SLAM-mediated effects in allergic asthma predominate by lymphocyte, macrophage, or SLAM-associated protein signaling-mediated mechanisms warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

The Costimulatory Molecule SLAM Is Critical for Pulmonary Allergic Responses

Wang

Campo²,

Ting³

et al. 2006

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

T-cell activation plays an essential role in the generation of the pulmonary inflammation that is manifest in allergic asthma. Optimal T-cell activation requires not only presentation of antigen with the major histocompatibility complex, but also concurrent signaling through costimulatory molecules. The costimulatory molecule SLAM (Signaling Lymphocytic Activation Molecule, CD150) is a glycoprotein expressed on activated lymphocytes and antigenpresenting cells. Disruption of the SLAM gene demonstrated that SLAM-induced signal transduction pathways regulate cytokine production by T helper (Th)2 cells and macrophages. Here we tested the postulate that the costimulatory molecule SLAM may be critical for allergic inflammation in a murine model. SLAM-deficient mice did not manifest allergen-induced bronchoalveolar lavage eosinophilia, increased serum IgE, or heightened airway responses compared with wild-type mice. Allergen-induced Th2 cytokines and Th1 cytokines were decreased in SLAM-deficient mice. These data support the concept that SLAM plays a crucial role in allergic responses.

show abstract

“…Because engagement of CD150 or CS1 was shown to trigger PI3K activation (17,(33)(34)(35), and this activation is mediated by EAT-2 in NK cells (17), we hypothesized that EAT-2 acts downstream of SLAM engagement to decrease IL-12 production in BMDC by blocking activation of the p38 MAPK and JNK pathways, through activation of the PI3K pathway. Consistent with this possibility, engagement of CD150 or CD84 led to significantly reduced levels of p38 MAPK and JNK, as well as increased levels of AKT phosphorylation following CD40 stimulation of BMDC, which was not seen for c1 congenic mouse strains with the NZB EAT-2 polymorphism.…”

Section: Discussionmentioning

confidence: 99%

Identification of the SLAM Adapter Molecule EAT-2 as a Lupus-Susceptibility Gene That Acts through Impaired Negative Regulation of Dendritic Cell Signaling

Talaei

Tao

Manion

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

We showed previously that C57BL/6 congenic mice with an introgressed homozygous 70 cM (125.6 Mb) to 100 cM (179.8 Mb) interval on c1 from the lupus-prone New Zealand Black (NZB) mouse develop high titers of antinuclear Abs and severe glomerulonephritis. Using subcongenic mice, we found that a genetic locus in the 88–96 cM region was associated with altered dendritic cell (DC) function and synergized with T cell functional defects to promote expansion of pathogenic proinflammatory T cell subsets. In this article, we show that the promoter region of the NZB gene encoding the SLAM signaling pathway adapter molecule EWS-activated transcript 2 (EAT-2) is polymorphic, which results in an ∼70% reduction in EAT-2 in DC. Silencing of the EAT-2 gene in DC that lacked this polymorphism led to increased production of IL-12 and enhanced differentiation of T cells to a Th1 phenotype in T cell–DC cocultures, reproducing the phenotype observed for DC from congenic mice with the NZB c1 70–100 cM interval. SLAM signaling was shown to inhibit production of IL-12 by CD40L-activated DCs. Consistent with a role for EAT-2 in this inhibition, knockdown of EAT-2 resulted in increased production of IL-12 by CD40-stimulated DC. Assessment of downstream signaling following CD40 cross-linking in the presence or absence of SLAM cross-linking revealed that SLAM coengagement blocked activation of p38 MAPK and JNK signaling pathways in DC, which was reversed in DC with the NZB EAT-2 allele. We conclude that EAT-2 negatively regulates cytokine production in DC downstream of SLAM engagement and that a genetic polymorphism that disturbs this process promotes the development of lupus.

show abstract

The role of SAP in murine CD150 (SLAM)-mediated T-cell proliferation and interferon γ production

Cited by 68 publications

References 56 publications

Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

Measles virus hemagglutinin triggers intracellular signaling in CD150-expressing dendritic cells and inhibits immune response

The Costimulatory Molecule SLAM Is Critical for Pulmonary Allergic Responses

Identification of the SLAM Adapter Molecule EAT-2 as a Lupus-Susceptibility Gene That Acts through Impaired Negative Regulation of Dendritic Cell Signaling

Contact Info

Product

Resources

About