Developmental Control of Endocytosis in Dendritic Cells by Cdc42

Garrett, Wendy S.; Chen, Limei; Kroschewski, Ruth; Ebersold, Melanie; Turley, Shannon J.; Trombetta, Sergio; Galán, Jorge E.; Mellman, Ira

doi:10.1016/s0092-8674(00)00038-6

Cited by 392 publications

(382 citation statements)

References 47 publications

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“…In the present work, we further characterize the earlier described capacity of iDC to internalize and process antigen for presentation on MHC class I [15][16][17]. We found that dispersed iDC can process exogenous OVA in an alternative, TAP-independent, BFA-and lactacystinresistant MHC class I pathway and that this function is rapidly lost as the cells mature in vitro.…”

Section: Introductionmentioning

confidence: 52%

Alternative processing for MHC class I presentation by immature and CpG‐activated dendritic cells

Chen

Jondal

2004

Eur J Immunol

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Exogenous proteins can be processed by antigen-presenting cells for the generation of MHC class I-restricted T cell responses. Where this occurs is not clear, although both transfer of internalized antigen into the cytosol and alternative processing in endolysosomes and phagosomes have been reported. Here we have studied the capacity of bone marrowderived mouse myeloid dendritic cells (DC) to process the OVA protein for peptide presentation by H2-K b . We have found that immature DC (iDC), both wild-type and transporter associated with antigen processing (TAP)-deficient cells, can transiently process OVA in a pathway which is resistant to inhibitors of the classical MHC class I pathway including the Golgi inhibitor Brefeldin A (BFA) and the proteasome inhibitor lactacystin. This alternative pathway is not found in subcultured DC with an intermediate maturity (imDC) or in resting, IL-3 expanded macrophages but can be re-expressed in imDC if these are activated by an immunostimulatory CpG oligonucleotide. Both iDC and CpG-activated DC were found to process OVA by regurgitation. In addition, we found that iDC secrete proteolytic enzymes into the supernatant, which can process OVA in the extracellular phase. These results suggest that multiple pathways exist for the processing of exogenous protein antigens into MHC class Ibinding peptides.

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Section: Introductionmentioning

confidence: 52%

Alternative processing for MHC class I presentation by immature and CpG‐activated dendritic cells

Chen

Jondal

2004

Eur J Immunol

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“…Thus, data obtained by use of exoenzyme C3 speak in favor of an important role of the DC's F-actin cytoskeleton without addressing the regulatory role(s) of individual GTPases. LPS exposure of immature bone marrow-derived murine DCs down-regulates active Cdc42 (13), while the same stimulus increases Cdc42 activity in murine splenic DCs (14). Rac1 (14) or Cdc42 (13) was found to be essential for the constitutive macropinocytosis of immature DCs.…”

Section: Endritic Cells (Dcs)mentioning

confidence: 96%

“…Rac1 (14) or Cdc42 (13) was found to be essential for the constitutive macropinocytosis of immature DCs. In the latter study, a down-regulated Cdc42 activity was functionally linked to the loss of macropinocytic activity in mature DCs (13). It is not decided whether the apparent discrepancy may relate to fundamental differences in Cdc42 regulation in different DC subtypes or may be due to variations in the detection levels of activated GTPases when they are bound to downstream targets in activated/mature DCs (15).…”

Section: Endritic Cells (Dcs)mentioning

confidence: 97%

“…In this study, we tried to define the functional roles of individual GTPases for the morphology and the Ag-presenting capacity of DCs grown from human stem cells in vitro. Microinjection of DCs with GTPase mutants, the commonly used experimental model for GTPase regulation (13,14,26), was no option for long-term studies with primary DCs and T cells, because only small cell numbers can be modified, and the effect of injected GTPases is short-lived only. In this study, we used a transfection system for CD34 ϩ stem cell-derived Langerhans cell (LC)-type DCs (referred to as DCs from now on) that allows sustained expression of transgenes.…”

Section: Endritic Cells (Dcs)mentioning

confidence: 99%

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Lipid Raft-Associated GTPase Signaling Controls Morphology and CD8+ T Cell Stimulatory Capacity of Human Dendritic Cells

Jaksits

Bauer

Kriehuber

et al. 2004

The Journal of Immunology

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Their eponymous morphology and unique ability to activate naive T cells are hallmark features of dendritic cells (DCs). Specific properties of the actin cytoskeleton may define both characteristics. In search for regulators that coordinate DC phenotype and function, we observed strongly increased expression of the actin-remodeling GTPases Cdc42 and Rac1 during DC development from human stem cells. Cdc42 and Rac1 are constitutively active in immature DCs, and their activity is further up-regulated by maturational stimuli such as LPS or CD40L. Activation of Rac1 is associated with its rapid recruitment into lipid rafts. Cdc42 is not recruited into rafts, but readily activated by raft-associated moieties. The functional interplay of rafts, GTPases, and cortical actin is further shown by GTPase activation and actin remodeling after pharmacological disruption of lipid rafts and by the loss of the actin-based DC morphology by transfection of dominant-negative Cdc42 and Rac1. Both Cdc42 and Rac1 also control the transport of essential immunostimulatory molecules to the DC surface. Transfection with dominant-negative GTPases led to reduced surface expression of MHC class I and CD86. Consecutively, DCs display a reduced stimulatory capacity for CD8+ T cells, whereas MHC class II-dependent stimulation of CD4+ T cells remains unperturbed. We conclude that Cdc42 and Rac1 signaling controls DC morphology and conditions DCs for efficient CD8+ T cell stimulation.

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“…In DCs exposed to Ag and maturational stimuli, such as LPS and TNF-␣, peptide loading is thought to occur in the MIIC, followed by transport of Ag-bound MHC class II molecules to the cell surface (4 -7). Concurrently, endocytosis is down-regulated, resulting in the accumulation of MHC class II/peptide complexes on the cell surface (8,9). These DC maturation-associated changes in MHC class II trafficking are critical for peptide Ag presentation.…”

Section: Endritic Cells (Dcs) 3 Capture Ags In Peripheral Tissuesmentioning

confidence: 99%

CD1 Molecules Efficiently Present Antigen in Immature Dendritic Cells and Traffic Independently of MHC Class II During Dendritic Cell Maturation

Cao

Sugita

Wel

et al. 2002

The Journal of Immunology

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Upon exposure to Ag and inflammatory stimuli, dendritic cells (DCs) undergo a series of dynamic cellular events, referred to as DC maturation, that involve facilitated peptide Ag loading onto MHC class II molecules and their subsequent transport to the cell surface. Besides MHC molecules, human DCs prominently express molecules of the CD1 family (CD1a, -b, -c, and -d) and mediate CD1-dependent presentation of lipid and glycolipid Ags to T cells, but the impact of DC maturation upon CD1 trafficking and Ag presentation is unknown. Using monocyte-derived immature DCs and those stimulated with TNF-α for maturation, we observed that none of the CD1 isoforms underwent changes in intracellular trafficking that mimicked MHC class II molecules during DC maturation. In contrast to the striking increase in surface expression of MHC class II on mature DCs, the surface expression of CD1 molecules was either increased only slightly (for CD1b and CD1c) or decreased (for CD1a). In addition, unlike MHC class II, DC maturation-associated transport from lysosomes to the plasma membrane was not readily detected for CD1b despite the fact that both molecules were prominently expressed in the same MIIC lysosomal compartments before maturation. Consistent with this, DCs efficiently presented CD1b-restricted lipid Ags to specific T cells similarly in immature and mature DCs. Thus, DC maturation-independent pathways for lipid Ag presentation by CD1 may play a crucial role in host defense, even before DCs are able to induce maximum activation of peptide Ag-specific T cells.

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Developmental Control of Endocytosis in Dendritic Cells by Cdc42

Cited by 392 publications

References 47 publications

Alternative processing for MHC class I presentation by immature and CpG‐activated dendritic cells

Alternative processing for MHC class I presentation by immature and CpG‐activated dendritic cells

Lipid Raft-Associated GTPase Signaling Controls Morphology and CD8+ T Cell Stimulatory Capacity of Human Dendritic Cells

CD1 Molecules Efficiently Present Antigen in Immature Dendritic Cells and Traffic Independently of MHC Class II During Dendritic Cell Maturation

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