MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223)

Andreae, Susanne; Buisson, Sandrine; Triebel, Frédéric

doi:10.1182/blood-2003-01-0273

Cited by 132 publications

(114 citation statements)

References 38 publications

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“…GA also interacts promiscuously with MHC class II molecules at the surface of living APCs (40). The latter study demonstrates that binding of GA to MHC class II molecules occurred very rapidly after GA application, i.e., GA binding at time = 0 (80%) was not different from that at time = 20 h. This contrasts with the present results showing delayed signal transduction with maximum Akt and ERK1/2 phosphorylation at 2 h. Because signal transduction induced by ligation of MHC class II molecules by antibodies, their natural ligand (LAG-3), or superantigens occurs within minutes (41)(42)(43), it is likely that GA signaling is mediated by other receptors/sensors. Moreover, contrasting with GA effects, IL-1β production is induced in monocytes upon ligation of MHC class II by antibodies, F(ab) from the latter, and superantigens (42,(44)(45)(46).…”

Section: Discussioncontrasting

confidence: 56%

Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

Carpintero

Brandt

Gruaz

et al. 2010

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

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Glatiramer acetate (GA), an immunomodulator used in multiple sclerosis (MS) therapy, induces the production of secreted IL-1 receptor antagonist (sIL-1Ra), a natural inhibitor of IL-1β, in human monocytes, and in turn enhances sIL-1Ra circulating levels in MS patients. GA is a mixture of peptides with random Glu, Lys, Ala, and Tyr sequences of high polarity and hydrophilic nature that is unlikely to cross the blood–brain barrier. In contrast, sIL-1Ra crosses the blood–brain barrier and, in turn, may mediate GA anti-inflammatory activities within the CNS by counteracting IL-1β activities. Here we identify intracellular signaling pathways induced by GA that control sIL-1Ra expression in human monocytes. By using kinase knockdown and specific inhibitors, we demonstrate that GA induces sIL-1Ra production via the activation of PI3Kδ, Akt, MEK1/2, and ERK1/2, demonstrating that both PI3Kδ/Akt and MEK/ERK pathways rule sIL-1Ra expression in human monocytes. The pathways act in parallel upstream glycogen synthase kinase-3α/β (GSK3α/β), the knockdown of which enhances sIL-1Ra production. Together, our findings demonstrate the existence of signal transduction triggered by GA, further highlighting the mechanisms of action of this drug in MS.

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Section: Discussioncontrasting

confidence: 56%

Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

Carpintero

Brandt

Gruaz

et al. 2010

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

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“…The interaction between LAG-3 on T cells and MHC II molecules on APCs delivers a negative signal to downregulate T cell proliferative and cytotoxic activities, thereby restraining the overexpansion of activated T cells and preventing the self-killing of APCs (17,19,21,37). Meanwhile, this interaction also imparts a positive signal to APCs and promotes the maturation of APCs (38,39), which enables APCs to raise more Ag-specific T cells. Therefore, the LAG-3/MHC II pathway may serve as an "amplifier" for the initiation of immune responses.…”

Section: Discussionmentioning

confidence: 99%

The Upregulation of LAG-3 on T Cells Defines a Subpopulation with Functional Exhaustion and Correlates with Disease Progression in HIV-Infected Subjects

Tian

Zhang

Qiu

et al. 2015

The Journal of Immunology

119

110

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T cells develop functional defects during HIV-1 infection, partially due to the upregulation of inhibitory receptors such as programmed death-1 (PD-1) and CTLA-4. However, the role of lymphocyte activation gene-3 (LAG-3; CD223), also known as an inhibitory receptor, in HIV infection remains to be determined. In this study, we revealed that LAG-3 on T cells delivers an inhibitory signal to downregulate T cell functionality, thereby playing an immunoregulatory role during persistent HIV-1 infection. We observed that HIV-1 infection results in a significant increase in LAG-3 expression in both the peripheral blood and the lymph nodes. The upregulation of LAG-3 is dramatically manifested on both CD4+ and CD8+ T cells and is correlated with disease progression. As expected, prolonged antiretroviral therapy reduces the expression of LAG-3 on both CD4+ and CD8+ T cells. The ex vivo blockade of LAG-3 significantly augments HIV-specific CD4+ and CD8+ T cell responses, whereas the overexpression of LAG-3 in T cells or the stimulation of LAG-3 on T cells leads to the reduction of T cell responses. Furthermore, most LAG-3 and PD-1 are expressed in different T cell subsets. Taken together, these data demonstrate that the LAG-3/MHC class II pathway plays an immunoregulatory role, thereby providing an important target for enhancing immune reconstitution in HIV-infected patients. Additionally, the LAG-3/MHC class II pathway may synergize with PD-1/PD ligand to enhance T cell–mediated immune responses.

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“…Engagement of class II HLA on the surface of APCs by TCR and non-TCR ligands activates signaling pathways in APCs that regulate their function and survival (23)(24)(25). For example, ligation of surface-expressed class II HLA molecules on APCs by superantigens activates the myeloid differentiation primary response gene 88 signaling pathway (26), inducing expression of proinflammatory cytokines (27).…”

Section: Drαmentioning

confidence: 99%

HLA-DRB111*and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

Ombrello¹,

Remmers²,

Tachmazidou³

et al. 2015

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

145

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Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10−17, odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10−5, OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10−16, OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11—HLA-DQA1*05—HLA-DQB1*03 haplotype [6.4 × 10−17, OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.

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MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223)

Cited by 132 publications

References 38 publications

Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

The Upregulation of LAG-3 on T Cells Defines a Subpopulation with Functional Exhaustion and Correlates with Disease Progression in HIV-Infected Subjects

HLA-DRB111*and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

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MHC class II signal transduction in human dendritic cells induced by a natural ligand, the LAG-3 protein (CD223)

Cited by 132 publications

References 38 publications

Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

Glatiramer acetate triggers PI3Kδ/Akt and MEK/ERK pathways to induce IL-1 receptor antagonist in human monocytes

The Upregulation of LAG-3 on T Cells Defines a Subpopulation with Functional Exhaustion and Correlates with Disease Progression in HIV-Infected Subjects

HLA-DRB1*11and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis

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Product

Resources

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HLA-DRB111*and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis