Transcription factor NF-κB regulates inducible CD83 gene expression in activated T lymphocytes

McKinsey, Timothy A.; Chu, Zhi-Liang; Tedder, Thomas F.; Ballard, Dean W.

doi:10.1016/s0161-5890(00)00099-7

Cited by 45 publications

(41 citation statements)

References 25 publications

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“…Significantly, promoters of various DC maturation marker genes such as CD83 and CD86 demonstrate the presence of canonical NF-B-binding sites thus implicating effects of NF-B on the functionality of DCs (52,53). As rigorously established, IB, implied as a strong negative feedback, tightly regulates activation of NF-B, thus effectuating a speedy turn off of the NF-B responses (54).…”

Section: Integration Of Pkc-mapk-nf-b Signaling Pathways During Tlr2 mentioning

confidence: 89%

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Ghorpade

Kaveri

Bayry

et al. 2011

Journal of Biological Chemistry

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Dendritic cells (DCs) as sentinels of the immune system are important for eliciting both primary and secondary immune responses to a plethora of microbial pathogens. Cooperative stimulation of a complex set of pattern-recognition receptors, including TLR2 and nucleotide-binding oligomerization domain (NOD)-like receptors on DCs, acts as a rate-limiting factor in determining the initiation and mounting of the robust immune response. It underscores the need for "decoding" these multiple receptor interactions. In this study, we demonstrate that TLR2 and NOD receptors cooperatively regulate functional maturation of human DCs. Intriguingly, synergistic stimulation of TLR2 and NOD receptors renders enhanced refractoriness to TGF-␤-or CTLA-4-mediated impairment of human DC maturation. Signaling perturbation data suggest that NOTCH1-PI3K signaling dynamics assume critical importance in TLR2-and NOD receptor-mediated surmounting of CTLA-4-and TGF-␤-suppressed maturation of human DCs. Interestingly, the NOTCH1-PI3K signaling axis holds the capacity to regulate DC functions by virtue of PKC␦-MAPK-dependent activation of NF-B. This study provides mechanistic and functional insights into TLR2-and NOD receptor-mediated regulation of DC functions and unravels NOTCH1-PI3K as a signaling cohort for TLR2 and NOD receptors. These findings serve in building a conceptual foundation for the design of improved strategies for adjuvants and immunotherapies against infectious diseases.

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Section: Integration Of Pkc-mapk-nf-b Signaling Pathways During Tlr2 mentioning

confidence: 89%

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Ghorpade

Kaveri

Bayry

et al. 2011

Journal of Biological Chemistry

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“…CD83 is known to be expressed by activated human B cells [13,14], and is also induced on a subpopulation of CD2 + /CD14 + monocytes upon activation with IFN-α [24]. Activated T cells also appear to express CD83 [25,26]. In mice, CD83 is expressed also by thymic epithelial cells, and has been shown to regulate the generation of CD4 + T cells [19].…”

Section: Discussionmentioning

confidence: 99%

CD83 is preformed inside monocytes, macrophages and dendritic cells, but it is only stably expressed on activated dendritic cells

Cao

Lee

2004

Biochemical Journal

147

125

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Human DCs (dendritic cells) express surface CD83 upon activation. Comparing the surface induction of CD83 with the upregulation of CD40, CD80 and CD86 during LPS (lipopolysaccharide)-induced DC maturation showed that CD83 induction occurred more rapidly. Despite the lack of CD83 on immature DCs, it was detected in these cells by Western blotting and flow cytometry. Indirect immunofluorescence revealed CD83 inside immature DCs in perinuclear regions. CD83 was absent on monocytes and macrophages, but it was detected inside these cells and found to be rapidly surface-expressed upon LPS-induced activation. Whereas CD83 expression on activated DCs was sustainable, its expression on monocytes and macrophages was transient. Optimal interleukin-4 co-stimulation during DC generation from monocytes was found to be essential for stable CD83 surface expression. CD83 was detected as 37 and 50 kDa forms in transfected 293T cells. Macrophages and immature DCs expressed the 37 kDa form, whereas mature DCs predominantly expressed the 50 kDa form. In monocytes, CD83 was detected as a 22 kDa detergent-insoluble form. The rapid CD83 surface induction on DCs and macrophages was blocked by brefeldin A, but not by cycloheximide, showing that fresh CD83 synthesis was not essential. Tunicamycin inhibited the expression of the 50 and 37 kDa CD83 forms, and also blocked CD83 surface expression on DCs and macrophages. PNGase F (peptide N-glycosidase F) digestion reduced the 37 and 50 kDa CD83 forms to 28 kDa. In summary, monocytes, macrophages and immature DCs contain preformed intracellular CD83, and its rapid surface expression upon activation is post-translationally regulated in a process involving glycosylation.

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“…This membrane-bound protein is also expressed, although to a significant lower extent, on activated T and B cells [7][8][9][10]. Moreover, a soluble form of CD83 is detectable at low levels in sera derived from healthy individuals, whereas in contrast, elevated levels are present in patients suffering from certain hematological malignancies [8,11].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

et al. 2009

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Fully mature DC and, to a lesser extent, activated T and B cells express CD83, a surface molecule that appears to fulfil an important role in efficient T-cell activation. Recently, it has been shown that CD83 mRNA is transported from the nucleus to the cytoplasm by an uncommon route, involving the cellular RNA-binding protein HuR and the nuclear export receptor CRM1. Moreover, the shuttle phosphoprotein APRIL (ANP32B) has been shown to be required for HuR-mediated nucleocytoplasmic translocation of the CD83 mRNA by acting as an adaptor that links HuR and CRM1. Here, we are able to report that casein kinase 2 (CK2) phosphorylates APRIL on residue threonine244 (Thr 244 ) and demonstrate that the CK2-specific inhibitor 4,5,6,7-tetrabromo-2-azabenzimidazole abolishes CD83 expression in activated Jurkat T cells by interfering with the nucleocytoplasmic translocation of CD83 mRNA. Depletion and knockdown studies demonstrate that the CK2 a 0 subunit is necessary for this regulation, whereas the CK2 a subunit seems to be dispensable. Taken together, the data presented significantly extend our knowledge of the complex regulation of CD83 mRNA processing and provides a novel strategy to interfere with CD83 expression.Key words: APRIL . Casein kinase 2 . CD83 . HuR . Leukocytes IntroductionMature DC are capable of sensitizing even naïve CD4 1 and CD8 1 T cells, and are therefore frequently termed ''nature's adjuvant''. Immature DC reside in the peripheral tissues and upon uptake of antigen and exposure to inflammatory stimuli, they migrate to the peripheral lymph nodes, where now fully matured, they induce antigen-specific T-cell response [1][2][3][4]. The DC maturation process includes the modulation of chemokine and chemokine receptors, as well as the up-regulation of several cytokines, costimulatory and adhesion molecules [5].Human CD83 serves as a major marker molecule for mature DC that belongs to the immunoglobulin super family [6,7]. This membrane-bound protein is also expressed, although to a significant lower extent, on activated T and B cells [7][8][9][10]. Moreover, a soluble form of CD83 is detectable at low levels in sera derived from healthy individuals, whereas in contrast, elevated levels are present in patients suffering from certain hematological malignancies [8,11]. Notwithstanding the fact that accumulating experimental evidence suggests that CD83 plays an important functional role in the regulation of DCmediated T-cell-specific immune response [12][13][14][15][16][17][18][19], the exact function of CD83 remains poorly understood [20][21][22]. Nevertheless, various disease-related findings suggest that CD83 holds great potential for future therapeutic application [23]. For example, EAE can be prevented in mice by applying a soluble form of CD83 [24]. Likewise, in rats, a positive therapeutic effect on experimental autoimmune myasthenia gravis has been reported by application of pentoxifylline, a drug that apparently interferes with CD83 expression [25,26]. Furthermore, CD83 1 DC were found to localize i...

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Transcription factor NF-κB regulates inducible CD83 gene expression in activated T lymphocytes

Cited by 45 publications

References 25 publications

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

CD83 is preformed inside monocytes, macrophages and dendritic cells, but it is only stably expressed on activated dendritic cells

Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

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