CD83 Expression Influences CD4+ T Cell Development in the Thymus

Fujimoto, Yoko; Tu, Lili; Miller, Ann S.; Bock, Cheryl B.; Fujimoto, Manabu; Doyle, Carolyn A.; Steeber, Douglas A.; Tedder, Thomas F.

doi:10.1016/s0092-8674(02)00673-6

Cited by 193 publications

(257 citation statements)

References 56 publications

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“…Studies of CD4 ϩ and CD8 ϩ T cell populations isolated from CD83 Ϫ/Ϫ mice contribute to this assumption. CD83 deficiency led to a strong reduction of peripheral CD4 ϩ T cells, whereas CD8 ϩ T cells were not affected (16). These results are well in line with the lack of CD83 expression on WT CD8 ϩ T cells even upon stimulation (Fig.…”

Section: Discussionsupporting

confidence: 85%

“…Its expression has been described in the brain and spleen (12) as well as in activated bone marrow-derived DCs (13) and activated B cells (14,15). Recent studies of mice deficient for CD83 have revealed that CD83 plays a central role in the thymic selection of double-positive thymocytes to single CD4-positive T cells, as these mice show a selective 75-90% reduction in peripheral CD4 ϩ T cells (16,17). Thus, CD83 expression on thymic epithelial cells seems to represent an additional regulatory component for CD4 ϩ T cell development in the thymus.…”

mentioning

confidence: 99%

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CD83 Expression in CD4+ T Cells Modulates Inflammation and Autoimmunity

Reinwald

Wiethe²,

Westendorf

et al. 2008

The Journal of Immunology

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The transmembrane protein CD83 has been initially described as a maturation marker for dendritic cells. Moreover, there is increasing evidence that CD83 also regulates B cell function, thymic T cell maturation, and peripheral T cell activation. Herein, we show that CD83 expression confers immunosuppressive function to CD4+ T cells. CD83 mRNA is differentially expressed in naturally occurring CD4+CD25+ regulatory T cells, and upon activation these cells rapidly express large amounts of surface CD83. Transduction of naive CD4+CD25− T cells with CD83 encoding retroviruses induces a regulatory phenotype in vitro, which is accompanied by the induction of Foxp3. Functional analysis of CD83-transduced T cells in vivo demonstrates that these CD83+Foxp3+ T cells are able to interfere with the effector phase of severe contact hypersensitivity reaction of the skin. Moreover, adoptive transfer of these cells prevents the paralysis associated with experimental autoimmune encephalomyelitis, suppresses proinflammatory cytokines IFN-γ and IL-17, and increases antiinflammatory IL-10 in recipient mice. Taken together, our data provide the first evidence that CD83 expression can contribute to the immunosuppressive function of CD4+ T cells in vivo.

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Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 99%

CD83 Expression in CD4+ T Cells Modulates Inflammation and Autoimmunity

Reinwald

Wiethe²,

Westendorf

et al. 2008

The Journal of Immunology

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“…Although its exact function is still unknown, various independent studies using soluble forms of CD83 or employing CD83-specific RNA interference provided evidence that this surface molecule is required for efficient DC-mediated T-cell activation [14][15][16][17]19]. Furthermore, it has been shown that CD4 1 single-positive thymocyte development is impaired in CD83 (CD83 À/À ) knockout mice, resulting in pronounced reduction of peripheral CD4 1 T cells [44]. Mainly for these reasons, CD83 is considered to be a ''regulatory molecule of the immune system with great potential for therapeutic application '' [23].…”

Section: Discussionmentioning

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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“…The process is accompanied by cytoskeletal reorganization, reduced phagocytic uptake, acquisition of cellular motility, migration to lymphoid tissues, enhanced T cell activation potential and the development of characteristic cytoplasmic extensions or "dendrites." Mature DCs express a number of specific markers that distinguish them from immature DCs such as CD83, a cell surface molecule involved in CD4 + T cell development and cellcell interactions (29,30) and DC-LAMP, a DC-specific lysosomal protein.…”

Section: Maturationmentioning

confidence: 99%

“…Real-time imaging of murine DCs and naive T cells in intact explanted lymph nodes reveals that a DC interacts with as many as 500 T cells/h (29,62,63). In the presence of antigen, stable and durable DC-T cell contacts form, with antigen-bearing DCs engaging more than 10 T cells at a time.…”

Section: Dc-t Cell Interactionsmentioning

confidence: 99%