The regulation of T cell homeostasis and autoimmunity by T cell–derived LIGHT

Wang, Jing; Lo, James C.; Foster, Amy; Yü, Ping; Chen, Helen M.; Wang, Yan; Tamada, Koji; Chen, Lieping; Fu, Yang–Xin

doi:10.1172/jci200113827

Cited by 208 publications

(34 citation statements)

References 54 publications

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“…The engagement of LIGHT and HVEM enhances the immune response by boosting T-cell proliferation and cytokine production [5,7,8]. Constitutive expression of LIGHT under the control of the CD2 promoter in transgenic mice causes hyperactivation of T cells and leads to autoimmune manifestations [9,10]. In contrast, blockade of LIGHT:HVEM interaction by soluble HVEM-Ig protein significantly reduces the incidence of diabetes in non-obese diabetic (NOD) mice [9].…”

Section: Introductionmentioning

confidence: 99%

Increased Heterologous Protein Expression in Drosophila S2 Cells for Massive Production of Immune Ligands/Receptors and Structural Analysis of Human HVEM

et al. 2015

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Many immune ligands and receptors are potential drug targets, which delicately manipulate a wide range of immune responses. We describe here the successful application of an efficient method to dramatically improve the heterologous expression levels in Drosophila Schneider 2 cells, which enables the high-throughput production of several important immune ligands/receptors for raising antibodies, and for the structural and functional analyses. As an example, we purified the protein and characterized the structure of the immune receptor herpesvirus entry mediator (HVEM, TNFRSF14). HVEM is a member of tumor necrosis factor receptor superfamily, which is recognized by herpes simplex virus glycoprotein D (gD) and facilitates viral entry. HVEM participates in a range of interactions with other cell surface molecules, including LIGHT, BTLA, and CD160 to modulate a wide range of immune processes in CD4(+) and CD8(+) T cells, as well as NK cells. Due to the involvement of HVEM in these diverse signaling interactions, crystal structures of HVEM in complex with gD or BTLA have been previously reported. Here, we report the structure of HVEM in the absence of any ligands.

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Section: Introductionmentioning

confidence: 99%

Increased Heterologous Protein Expression in Drosophila S2 Cells for Massive Production of Immune Ligands/Receptors and Structural Analysis of Human HVEM

et al. 2015

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“…LIGHT may regulate T cell activation because it has been shown to mediate T cell costimulation (14), and overexpression of LIGHT results in T cell hyperactivation and autoimmunity (19,20). As such, inhibition of LIGHT was an obvious candidate mechanism to explain the activity of LTβR-Ig in T cell-based systems.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies examining LIGHT-overexpressing mice suggest that this TNF family member may be involved in T cell-driven autoimmunity (19,20). Because (a) Pooled CD4 + T cells were isolated at D10 from rats in the EAE model (n = 5), stimulated in vitro with irradiated splenocytes, and indicated concentrations of MBP-peptide and proliferation measured by 3 H-thymidine incorporation.…”

Section: Efficacy Of Ltβr-ig In Rat Eae Is Dependent On Ltαβ Binding mentioning

confidence: 99%

“…Transgenic mice expressing LIGHT on T cells develop an autoimmune-like phenotype dominated by intestinal disease, thus LIGHT expression may contribute to T cell-based pathology (19,20). Because LTβR-Ig is an effective LIGHT inhibitor, it is reasonable to assume that LIGHT binding by LTβR-Ig contributes to its aforementioned efficacy in attenuating autoimmune disease.…”

Section: Introductionmentioning

confidence: 99%

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A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT

Gommerman¹,

Giza²,

Perper³

et al. 2003

J. Clin. Invest.

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In studies using genetically deficient mice, a role for the lymphotoxin (LT) system in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) has remained controversial. Here, we have reassessed this conclusion by using a fusion protein decoy that blocks the LT pathway in vivo without evoking the developmental defects inherent in LT-deficient mice. We have found that inhibition of the LT pathway prevented disease in two models of EAE that do not rely on the administration of pertussis toxin. Surprisingly, disease attenuation was due to specific blockade of LTαβ binding rather than the binding of LIGHT to its receptors. In a third system that requires pertussis toxin, LT inhibition did not affect disease, as was observed when the same model was used with LT-deficient mice. Disease prevention in pertussis toxin-free models was associated with defects in T cell responses and migration. When the DO11.10 T cell transgenic system was used, inhibition of the LT pathway was shown to uncouple T cell priming from T cell recall responses. Therefore, it is hypothesized that the LT pathway and its ability to maintain lymphoid microenvironments is critical for sustaining late-phase T cell responses in multiple sclerosis.

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“…Lack of LIGHT led to a considerable impairment of proliferative responses in CD3 + and CD8 + T cells [7]. Dysregulation of the LIGHT activity ultimately resulted in the breakdown of peripheral tolerance [8]. Furthermore, the activity could induce not only autoimmune diseases such as graft versus host disease [9] and imunoglobulin A nephropathy [10], but also inflammatory diseases such as rheumatoid arthritis [11,12] and Crohn's disease [13].…”

Section: Introductionmentioning

confidence: 99%

Promoter sequence variants of LIGHT are associated with female vascular dementia

2008

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LIGHT (homologous to L ymphotoxins, exhibits I nducible expression, and competes with herpes simplex virus G lycoprotein D for H erpes virus entry mediator, a receptor expressed by T lymphocytes) is implicated in the inflammation by disrupted T cell homeostasis, primarily at a transcriptional level. We investigated the association of LIGHT promoter with ischemic stroke and vascular dementia induced by such inflammation. We determined transcription factor binding sites altered by promoter SNPs using transcription factor prediction programs. Six common haplotypes composed of the selected SNPs (C-770T, G-607T, G-543A, and A-399G) were used for the assay of reporter activity. The most frequent haplotype construct, CGGA, induced the highest luciferase activity. The haplotype TTGA showed the lowest expression with 0.39-fold activity (P < 0.001) of CGGA. The substitution from C to T at the locus of C-770T (TGGA) decreased the reporter activity by 47% (P < 0.001). The SNPs and haplotypes were further investigated to see their association with ischemic stroke and vascular dementia in 455 controls and 478 patients. Significant association with vascular dementia was shown in the allele T of C-770T (odds ratio [OR] = 1.54; P < 0.05) and the haplotype TTGA (OR = 10.59; P < 0.05) in females. We concluded that the allele T of C-770T and the haplotype TTGA of the promoter SNPs in LIGHT gene might decrease the expression of LIGHT and subsequently increase the susceptibility to vascular dementia in females.

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The regulation of T cell homeostasis and autoimmunity by T cell–derived LIGHT

Cited by 208 publications

References 54 publications

Increased Heterologous Protein Expression in Drosophila S2 Cells for Massive Production of Immune Ligands/Receptors and Structural Analysis of Human HVEM

Increased Heterologous Protein Expression in Drosophila S2 Cells for Massive Production of Immune Ligands/Receptors and Structural Analysis of Human HVEM

A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT

Promoter sequence variants of LIGHT are associated with female vascular dementia

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