Interactions of T Cells with Fibroblast-Like Synoviocytes: Role of the B7 Family Costimulatory Ligand B7-H3

Tran, Chinh; Thacker, Seth G.; Louie, Deanna M.; Oliver, Jennifer A.; White, Peter; Endres, Judith; Urquhart, Andrew G.; Chung, Kevin C.; Fox, David A.

doi:10.4049/jimmunol.180.5.2989

Cited by 60 publications

(58 citation statements)

References 50 publications

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“…Interestingly, T-cell activation was also shown to result in a heightened degree of interaction between these activated T-cells and fibroblast-like synoviocytes (FLS) [23]. Additionally, activation and perpetuation of synoviocyte, chondrocyte and even T-cell activation in the RA joint may also involve the activity of complement proteins which were recently shown to be integral part of T-cell activation process in specific lines of transgenic mice [24].…”

Section: T-cell Activation In Ra: Effect On Synoviocytes and Chondrocmentioning

confidence: 98%

Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways

Malemud¹

2011

aiaaamc

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A skewed repertoire of pro-inflammatory cytokines produced by the T h 1 subset, one of the hallmarks of rheumatoid arthritis (RA), is characterized by an overabundance of pro-inflammatory cytokines. Tumor necrosis factor-, interleukin-1 (IL-1), IL-6, IL-7, IL-8, IL-21, IL-12/IL-23, IL-15, IL-17, IL-18, IL-32, and interferon-are primarily responsible for immune-mediated inflammation of RA by activating Janus kinases (JAK) -1, -2, -3, p38 kinase, C-Jun-Nterminal kinase, extracellular signal-regulated kinase 1/2 and the phosphatidylinosotide-3-kinase/Akt/mTor pathways. Activation of these signaling pathways results in up-regulation of pro-inflammatory cytokines, cyclooxygenase-2, matrix metalloproteinases, pro-angiogenesis proteins and anti-apoptosis proteins, the latter resulting in abnormal survival of activated T-and B-cells. Further, IL-17 also regulates the differentiation of CD4 + T-helper cells by inducing a T h 17 T-cell subset, and a subpopulation of T-regulatory (T reg ) cells. Although T reg cells are sufficiently abundant in RA synovial fluid, they fail to induce immune tolerance suggesting a functional deficiency likely coupled to putative protein kinase signaling abnormalities. The results of in vitro and studies in animal models of arthritis have indicated that inhibiting individual signaling pathways can blunt the synthesis of several of the pro-inflammatory biomarkers characteristic of human RA pathology. However, RA clinical trials indicated that small molecule inhibitors of JAK-1, -2-, 3 and/or p38 kinase while exhibiting acceptable safety and tolerability profiles have only marginal and transient clinical effectiveness. These results suggested that future RA clinical studies using these or other kinase inhibitors will have to consider strategies designed to simultaneously inhibit multiple kinase pathways.

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Section: T-cell Activation In Ra: Effect On Synoviocytes and Chondrocmentioning

confidence: 98%

Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways

Malemud¹

2011

aiaaamc

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“…This is in part through macrophage secretion of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF), which in turn activates synovial fibroblasts to produce inflammatory cytokines and chemokines like IL-6 and IL-8, tissue-destructive factors such as MMPs, and to assume an invasive and tissue-destructive phenotype (10–15). Although synovial fibroblast contribution to the inflammatory milieu and tissue destruction is well appreciated and their ability to activate T cells and promote B cell survival have been characterized (16, 17), the effects of synovial fibroblasts on macrophage function in an inflammatory setting have not been elucidated (12). It remains to be determined whether under normal physiologic conditions synovial fibroblasts function, like other mesenchymal stromal cells, to limit inflammatory reactions and whether deregulation of this capacity contributes to RA pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Modulation of TNF-Induced Macrophage Polarization by Synovial Fibroblasts

Donlin

Jayatilleke

Γιαννοπούλου³

et al. 2014

The Journal of Immunology

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Mesenchymal stromal cells have emerged as powerful modulators of the immune system. Here we explored how the human macrophage response to tumor necrosis factor (TNF) is regulated by human synovial fibroblasts, the representative stromal cell type in the synovial lining of joints that become activated during inflammatory arthritis. We found that synovial fibroblasts strongly suppressed TNF-mediated induction of an interferon (IFN)-β autocrine loop and downstream expression of IFN-stimulated genes (ISGs), including chemokines CXCL9 and CXCL10 that are characteristic of classical macrophage activation. TNF induced the production of soluble synovial fibroblast factors that suppressed the macrophage production of IFN-β, and cooperated with TNF to limit the responsiveness of macrophages to IFN-β by suppressing activation of Jak-STAT signalling. Genome-wide transcriptome analysis showed that co-cultured synovial fibroblasts modulate the expression of approximately one third of TNF-regulated genes in macrophages, including genes in pathways important for macrophage survival and polarization towards an alternatively activated phenotype. Pathway analysis revealed that gene expression programs regulated by synovial fibroblasts in our co-culture system were also regulated in rheumatoid arthritis (RA) synovial macrophages, suggesting that these fibroblast-mediated changes may contribute to RA pathogenesis. This work furthers our understanding of the interplay between innate immune and stromal cells during an inflammatory response, one that is particularly relevant to inflammatory arthritis. Our findings also identify modulation of macrophage phenotype as a new function for synovial fibroblasts that may prove to be a contributing factor in arthritis pathogenesis.

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“…Rheumatoid arthritis (RA) 3 is a systemic autoimmune disorder characterized by chronic inflammatory responses that primarily attack synovial membranes (1,2). The synovial environment in RA is comprised of a complex mix of cell types including T cells, B cells, neutrophils, monocytes/macrophages, and fibroblast-like synoviocytes (3).…”

mentioning

confidence: 99%

“…The synovial environment in RA is comprised of a complex mix of cell types including T cells, B cells, neutrophils, monocytes/macrophages, and fibroblast-like synoviocytes (3). The interplay among these cell types is known to contribute significantly to disease pathophysiology (4).…”

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confidence: 99%

Preferential Induction of the T Cell Auxiliary Signaling Molecule B7-H3 on Synovial Monocytes in Rheumatoid Arthritis

Yoon¹,

Chung

Yoo

et al. 2016

Journal of Biological Chemistry

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B7-H3, a newly identified B7 family member, has functional duality as a co-stimulator and co-inhibitor that fine-tunes T cell-mediated immune responses. Given that B7-H3 expression on human monocytes and dendritic cells is enhanced by inflammatory cytokines, its potential inmmunoregulatory role at sites of inflammation has been suggested. Further, monocytes play crucial roles in the pathophysiology of various inflammatory disorders including autoimmune diseases; however, the immunological role of B7-H3 in rheumatoid arthritis (RA) has not been defined. Thus, we aimed to investigate the possible roles of monocyte B7-H3 in the pathogenesis of RA. Synovial monocytes, but not peripheral monocytes, in RA patients predominantly express surface B7-H3. The 4Ig isoform of B7-H3 is exclusively induced on the cell surface, whereas the 2Ig B7-H3 isoform is constitutively expressed in the intracytoplasmic region of both peripheral and synovial monocytes. B7-H3 knockdown experiments reveal that surface B7-H3 has an inhibitory effect on IFN-␥ production in CD4 memory cells. Moreover, surface B7-H3 expression on synovial monocytes inversely correlates with RA clinical parameters. Our findings demonstrate that activation-induced B7-H3 expression on synovial monocytes has the potential to inhibit Th1-mediated immune responses and immunomodulatory roles affecting RA pathogenesis.

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Interactions of T Cells with Fibroblast-Like Synoviocytes: Role of the B7 Family Costimulatory Ligand B7-H3

Cited by 60 publications

References 50 publications

Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways

Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways

Modulation of TNF-Induced Macrophage Polarization by Synovial Fibroblasts

Preferential Induction of the T Cell Auxiliary Signaling Molecule B7-H3 on Synovial Monocytes in Rheumatoid Arthritis

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