Dendritic Cells

immune responses through their ability to mingle with and activate naïve T cells (1, 2). The differentiation of bone marrowderived precursors toward DC lineages and the functional plasticity necessary for an effective spectrum of DC͞T cell interactions is tightly regulated. Identification of individual gene products that are essential to normal DC differentiation and function has provided critical insights for understanding DC biology and for therapeutic modulation of DCs. The clearest example of such a gene product is the NF-B component RelB. Expression of RelB appears late in embryogenesis and is concentrated in the thymus and secondary lymphoid organs: specifically, in interdigitating DCs (iDCs) (3). Deletion of relB resulted in the virtual absence of iDCs with accompanying deficits in cognate immunity (4,5). Functional analysis of the remaining DCs or ex vivo derivation of relB Ϫ/Ϫ DCs revealed failure to up-regulate MHC and costimulatory proteins and deficiency in the capacity to stimulate naïve T cells, cross-present MHC I-restricted peptides, and facilitate Ig isotype switching (6). Significantly, RelB-deficient bone marrow-derived DCs (BMDCs) or BMDCs in which RelB activity is inhibited have the potential to induce antigen-specific immune tolerance in vivo (7).RelB intracellular levels and signaling are enhanced during DC maturation and participate in up-regulation of immunostimulatory proteins (8, 9). Transcriptional regulation of relB has not been extensively studied, although it is known to be inducible by means of NF-B response elements (10). We observed reduced intracellular levels of RelB in BMDCs generated in the presence of the active form of vitamin D 3 , 1␣,25-dihydroxyvitamin D 3 (1␣,25(OH) 2 D 3 ), and related analogs (D 3 analogs) (11,12). This effect depended on expression of the vitamin D receptor (VDR), which is a member of the nuclear receptor (NR) family of DNA binding proteins, and was mediated through binding of VDR͞retinoic acid X receptor ␣ (RXR␣) to vitamin D response elements (VDREs) in the promoter (12). These findings added to a growing body of evidence linking 1␣,25(OH) 2 D 3 ͞VDR to negative regulation of Th1-type immune responses and to inhibition of DC maturation (13-16). The implications of this literature are best exemplified by animal models (allograft rejection, autoimmune diabetes mellitus, and experimental allergic encephalomyelitis) that are ameliorated by 1␣,25(OH) 2 D 3 or D 3 analogs (13-17), by evidence that D 3 analog-conditioned DCs mediate immune tolerance in vivo (13)(14)(15)(16)18), and by epidemiologic studies that identify VDR genotype and vitamin D status as risk factors for autoimmunity (19,20).The interaction of VDR with chromosomal DNA is necessary for positive transcriptional responses, but NR association with additional proteins (coactivators, corepressors, and histone-modifying enzymes) is also crucial (21,22). Although transcriptional suppression by 1␣25(OH) 2 D 3 ͞VDR may be mediated by competitive displacement of positive regulatory factors, activ...

Section: Endritic Cells (Dcs) Occupy a Unique Role In Initiatingmentioning

confidence: 99%

Regulation of relB in dendritic cells by means of modulated association of vitamin D receptor and histone deacetylase 3 with the promoter

Dong

Lutz

Schroeder

et al. 2005

“…This process is accompanied by a marked cellular reorganization (1,2). Redistribution of MHC class II molecules (MHC class II) from late endosomal compartments to the plasma membrane (3) represents one of the major functional events observed during the acquisition of the immunostimulatory function by mDCs.…”

mentioning

confidence: 99%

MHC class II stabilization at the surface of human dendritic cells is the result of maturation-dependent MARCH I down-regulation

Gassart

Camosseto

Thibodeau

et al. 2008

214

278

In response to Toll-like receptor ligands, dendritic cells (DCs) dramatically enhance their antigen presentation capacity by stabilizing at the cell-surface MHC II molecules. We demonstrate here that, in human monocyte-derived DCs, the RING-CH ubiquitin E3 ligase, membrane-associated RING-CH I (MARCH I), promotes the ubiquitination of the HLA-DR ␤-chain. Thus, in nonactivated DCs, MARCH I induces the surface internalization of mature HLA-DR complexes, therefore reducing their stability and levels. We further demonstrate that the maturation-dependent down-regulation of MARCH I is a key event in MHC class II up-regulation at the surface of LPS-activated DCs. MARCH I is, therefore, a major regulator of HLA-DR traffic, and its loss contributes to the acquisition of the potent immunostimulatory properties of mature human DCs.antigen presentation ͉ ubiquitin ligase ͉ endocytosis ͉ LPS ͉ TLR A ctivation of dendritic cells (DCs) by invading pathogens involves a process of maturation that converts an immature DC (iDC) to a mature DC (mDC) and a subsequent Toll-like receptor (TLR)-mediated immune response. This process is accompanied by a marked cellular reorganization (1, 2). Redistribution of MHC class II molecules (MHC class II) from late endosomal compartments to the plasma membrane (3) represents one of the major functional events observed during the acquisition of the immunostimulatory function by mDCs. Recently in mouse DCs, ubiquitination of lysine-225 in the cytoplasmic tail of MHC II ␤-chain has been shown to be determinant for the targeting and accumulation of the mature form of MHC II in the lysosomes of iDCs (4, 5). Interestingly, ubiquitination of MHC II in murine DCs ceases on maturation, thus contributing to the increased level of MHC II at the cell surface (4, 5). Membrane-associated RING-CH (MARCH) proteins represent a family of E3 ubiquitin ligases, which all contain a variant catalytical RING-finger domain (RING-CH domain, C4HC3) located at the N terminus (6-10). It has been recently reported that transgenic overexpression of MARCH VIII/c-MIR in mouse splenic antigen-presenting cells (APCs) leads to internalization of surface CD86/B7-2 and MHC II, and subsequent lysosomal degradation (10). Furthermore, deletion of MARCH I, another E3 ubiquitin ligase, promoted an increase of surface MHC II levels in mouse B cells, although a direct implication of this ligase in the process of MHC II internalization was excluded (11). We identify here human MARCH I as a potent regulator of HLA-DR surface expression and explore its role during human monocyte-derived DC (MoDC) activation. We further show that MARCH I expression is lost at late stages of DC maturation and thereby participates in the stabilization of peptideloaded HLA-DR at the cell surface. Our observations suggest that MARCH I is essential to coordinate MHC II-restricted antigen presentation during human DC activation by TLR ligands. Results MHC Class II Ubiquitination Is Regulated in MoDCs.The subcellular localization of MHC class II (HLA-DR) in CD14 ϩ M...

“…Immature DCs residing in tissues endocytose soluble antigens, microbes, or apoptotic cells, and receive microbial or inflammatory maturation cues depending on the type of pathogen and the nature and extent of tissue damage (1)(2)(3). Maturing DCs migrate to lymph nodes via afferent lymphatics where they complete their maturation and present peptides derived from protein degradation on MHC class I and class II molecules to CD8 and CD4 T cells, respectively (2). The type and composition of maturation signals received by DCs determine whether they induce productive T cell responses or tolerance (4,5).…”

mentioning

confidence: 99%

Efficient cross-priming of tumor antigen-specific T cells by dendritic cells sensitized with diverse anti-MICA opsonized tumor cells

Groh

Cioca

et al. 2005

D endritic cells (DCs) have a central role in the initiation and control of T cell-mediated immunity. Immature DCs residing in tissues endocytose soluble antigens, microbes, or apoptotic cells, and receive microbial or inflammatory maturation cues depending on the type of pathogen and the nature and extent of tissue damage (1-3). Maturing DCs migrate to lymph nodes via afferent lymphatics where they complete their maturation and present peptides derived from protein degradation on MHC class I and class II molecules to CD8 and CD4 T cells, respectively (2). The type and composition of maturation signals received by DCs determine whether they induce productive T cell responses or tolerance (4, 5).Because of their potent immunostimulatory capacity, there is much interest in employing DCs as tumor vaccines to induce effector and long-term memory CD4 and CD8 T cells with broad tumor antigen (TA) specificities (6-8). Early-stage trials using ex vivo TA-loaded and matured monocyte-or CD34 ϩ progenitorderived DCs have provided some evidence for clinically beneficial immunostimulatory effects (9, 10). However, many variables remain to be explored, including antigen sources and modes of DC antigen-loading. Most commonly, DCs are pulsed with synthetic TA-derived MHC-binding peptides (11,12). This approach is constrained by limited knowledge of TA, their natural and immunoselected variation within and among tumors, and by the MHC allele-specific restrictions of peptide-binding, thus producing narrow repertoires of antigen-specific T cells. Other methods include transfection of DCs with tumor-derived RNA, the use of viral vectors for expression of TA, and facilitating DC uptake of tumorderived exosomes, apoptotic tumor cells, or recombinant proteins for antigen processing and presentation (13)(14)(15)(16)(17)(18)(19). Moreover, DC expression of Ig Fc receptors (Fc␥R) can be exploited for targeting immune complexes and antibody-coated tumor cells to DCs (20,21). Exposure of DCs to anti-syndecan mAb-opsonized myeloma cells promotes efficient in vitro cross-priming of cytotoxic T lymphocytes, yielding results that are superior to cross-presentation of TA from apoptotic tumor cells (22).This immunization mode is appealing because it may operate in vivo and contribute to the beneficial effects of some antibody-based cancer therapies (23,24). Hence, antibody targeting of surface molecules that are absent from most cell types and tissues but are frequently tumor-associated could be a viable approach to inducing tumor immunity. Suitable candidate molecules are MHC class I chain-related proteins A (MICA) and B (MICB), which are distantly related to MHC class I and function as ligands of the NKG2D receptor on natural killer cells and T cell subsets (25,26). In healthy individuals, the tissue distribution of MIC is restricted to variable areas of gastrointestinal epithelium (25, 27). However, MICs are abundantly expressed in many lung, breast, kidney, ovarian, prostate, gastric, and colon carcinomas, and melanomas, as well as in certai...