Fibroblasts stimulated via HLA-II molecules produce prostaglandin E2 and regulate cytokine production from helper T cells

Abstract

Fibroblasts act as important immune regulatory cells via their ability to cross-talk with T cells accumulating in lesions.Our previous study showed that fibroblasts produce several cytokines and chemokines by crosslinking HLA class II (HLA-II) molecules with monoclonal antibodies or by making T-cell receptor-peptide-HLA complexes. It is thus conceivable that the interaction of T cells and fibroblasts via HLA-II affects fibroblast responses to stimuli. This study used human gingival fibroblasts (HGF) to investigate possible effects of these fibroblast-derived soluble factors on the differentiation of naïve T cells and on the subsequent fibroblast responses. After mixed lymphocyte reaction culture between naïve T cells and allogeneic dendritic cells in the presence of culture supernatant from HGF stimulated via HLA-DQ molecules (DQ-sup), but not via DR, T cells exhibited a Th2-shifted phenotype, thereby producing quantitatively more IL-13 and IL-5 compared with interferon-g. Astonishingly, analyses to identify possible factors affecting the Th2 polarization secreted from HLA-IIstimulated HGF, prostaglandin E 2 , was detected only in DQ-sup. The Th2 polarization of naïve T cells was blocked in the presence of supernatants from indomethacin-treated HGF with HLA-DQ stimulation. In addition, we found that the culture supernatants of Th cells activated following mixed lymphocyte reaction culture in the presence of DQ-sup had the potential to induce gene expression of type I and III collagens in HGF. These results suggested that fibroblasts stimulated via HLA-DQ molecules promote Th2 polarization in Th-cell responses and showed the counter activation of collagen synthesis, implicating orchestrated responses among these cells in the fibrosis of chronic inflammatory lesions.

Interaction between Treg Apoptosis Pathways, Treg Function and HLA Risk Evolves during Type 1 Diabetes Pathogenesis

“…Thus, by switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of Tregs [44]. There is evidence that HLA expression can be induced in an environment rich in inflammatory cytokines [45], [46], suggestive of type of environment in the islets of a person progressing towards total beta-cell destruction. Furthermore, as human T lymphocytes are one of cell types that express HLA class II molecules following activation, these molecules on activated T cells could either affect the activity of T cells or they could provide signals that modulate T-cell functioning.…”

“…Furthermore, as human T lymphocytes are one of cell types that express HLA class II molecules following activation, these molecules on activated T cells could either affect the activity of T cells or they could provide signals that modulate T-cell functioning. If allogeneic dendritic cells expressing HLA-DQ (not HLA-DR) stimulate naïve T cells, they will shift towards Th2 phenotype [46]. As both HLA-DQ and HLA-DR genes, latter known as an activation marker, are down-regulated in Tregs from T1D subjects, it is possible that in T1D subjects, Tregs in the periphery have an activation defect, due to which they fail to exert suppressive function.…”

Antibodies in Transplantation: The Effects of HLA and Non-HLA Antibody Binding and Mechanisms of Injury

“…Cells become activated and proliferate or undergo apoptosis depending on which intracellular pathway is predominantly activated [120–122]. Fibroblasts stimulated through HLA II increase production of prostaglandin E [123], RANTES, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, and GROα [124, 125], through Janus kinase (JNK) and FAK signaling [126]. These HLA II-induced soluble factors produced by fibroblasts could promote proliferation of endothelial cells [124].…”

Controlling the Origins of Inflammation with a Photoactive Lipopeptide Immunopotentiator

“…[30,31] At am inimum, trans activation of fibroblasts can occur from BMDCs through TNF,w hile BMDCs can be stimulated by fibroblast prostanoids,s uch as prostaglandin E 2 . [32] We measured TNF obtained from mixed populations of BMDCs and fibroblasts relative to isolated populations,while using TRIGIR to vary the location of TLR signal transduction, thereby varying the origin of inflammation (Figure 2B). This approach allowed quantification of TNF production arising from interaction of BMDCs with immunostimulant relative to trans activation of BMDCs by fibroblasts or intercellular signaling between BMDCs.W e considered each cell type (fibroblasts and BMDCs) along with each cell type tagged with equimolar amounts of TRIGIR probe (tagged-fibroblasts and tagged-BMDCs).…”