A Role for Lipid Bodies in the Cross-presentation of Phagocytosed Antigens by MHC Class I in Dendritic Cells

Bougnères, Laurence; Helft, Julie; Tiwari, Sangeeta; Vargas, Pablo Agustín; Chang, Benny; Chan, Lawrence; Campisi, Laura; Lauvau, Grégoire; Hugues, Stéphanie; Kumar, Pradeep; Kamphorst, Alice O.; Dumenil, Ana Maria Lennon; Nussenzweig, Michel C.; MacMicking, John D.; Amigorena, Sébastian; Guermonprez, Pierre

doi:10.1016/j.immuni.2009.06.022

Cited by 149 publications

(173 citation statements)

References 49 publications

(84 reference statements)

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“…These structures did not costain with markers of the endoplasmic reticulum (ER) (ER tracker), mitochondria (Mitotracker), lysosomes, or late endosomes (LAMP1). Based on a similar staining pattern recently reported for the mouse interferongamma induced GTPase Igtp in dendritic cells (29), we tested for costaining with the lipid droplet (LD) marker BODIPY 493/503 and indeed found colocalization with GIMAP2 (Fig. 4 A and B).…”

Section: Resultsmentioning

confidence: 76%

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

Schwefel

Fröhlich²,

Eichhorst³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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GTPases of immunity-associated proteins (GIMAPs) are a distinctive family of GTPases, which control apoptosis in lymphocytes and play a central role in lymphocyte maturation and lymphocyte-associated diseases. To explore their function and mechanism, we determined crystal structures of a representative member, GIMAP2, in different nucleotide-loading and oligomerization states. Nucleotide-free and GDP-bound GIMAP2 were monomeric and revealed a guanine nucleotide-binding domain of the TRAFAC (translation factor associated) class with a unique amphipathic helix α7 packing against switch II. In the absence of α7 and the presence of GTP, GIMAP2 oligomerized via two distinct interfaces in the crystal. GTP-induced stabilization of switch I mediates dimerization across the nucleotide-binding site, which also involves the GIMAP specificity motif and the nucleotide base. Structural rearrangements in switch II appear to induce the release of α7 allowing oligomerization to proceed via a second interface. The unique architecture of the linear oligomer was confirmed by mutagenesis. Furthermore, we showed a function for the GIMAP2 oligomer at the surface of lipid droplets. Although earlier studies indicated that GIMAPs are related to the septins, the current structure also revealed a strikingly similar nucleotide coordination and dimerization mode as in the dynamin GTPase. Based on this, we reexamined the relationships of the septin-and dynamin-like GTPases and demonstrate that these are likely to have emerged from a common membrane-associated dimerizing ancestor. This ancestral property appears to be critical for the role of GIMAPs as nucleotide-regulated scaffolds on intracellular membranes. G protein | protein structure

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Section: Resultsmentioning

confidence: 76%

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

Schwefel

Fröhlich²,

Eichhorst³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Importantly, our study revealed that virally infected CD103 + DCs accumulate in the MLNs of Ifnar1 -/-mice but are absent from the MLNs of Ifnar1 +/+ mice infected with NS1-GFP, suggesting that type I IFN not only protects DCs from viral infection, but also protect mice from systemic viral dissemination. In addition to its key anti-viral effect, type I IFN was shown to promote DC maturation (26,27) and enhance the cross-presentation potential of DCs (28). Together, these results suggest that type I IFN signaling may simultaneously activate the acquisition of an anti-viral state while promoting DC capacity to cross-present antigens and cross-prime adaptive T cell responses.…”

Section: Discussionmentioning

confidence: 91%

Cross-presenting CD103+ dendritic cells are protected from influenza virus infection

Helft

Manicassamy

Guermonprez³

et al. 2012

J. Clin. Invest.

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224

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CD8 + cytotoxic T cells are critical for viral clearance from the lungs upon influenza virus infection. The contribution of antigen cross-presentation by DCs to the induction of anti-viral cytotoxic T cells remains controversial.Here, we used a recombinant influenza virus expressing a nonstructural 1-GFP (NS1-GFP) reporter gene to visualize the route of antigen presentation by lung DCs upon viral infection in mice. We found that lung CD103 + DCs were the only subset of cells that carried intact GFP protein to the draining LNs. Strikingly, lung migratory CD103 + DCs were not productively infected by influenza virus and thus were able to induce virus-specific CD8 + T cells through the cross-presentation of antigens from virally infected cells. We also observed that CD103 + DC resistance to infection correlates with an increased anti-viral state in these cells that is dependent on the expression of type I IFN receptor. These results show that efficient cross-priming by migratory lung DCs is coupled to the acquisition of an anti-viral status, which is dependent on the type I IFN signaling pathway. IntroductionThe identification of the mechanisms that control the initiation of anti-influenza virus CD8 + T cell responses that clear viral infections requires knowledge of the identity of the APCs and the location and time of antigen presentation by APCs to T lymphocytes. In viral infections, DCs could potentially acquire viral antigens through direct infection (direct MHC-I presentation pathway) or through the acquisition of exogenous antigens by phagocytosis of virally infected cells or viral particles (cross-presentation pathway). Efficient cross-priming is easily demonstrated in mouse models with an impaired direct antigen presentation pathway (1-3). In addition, genetic deletion of the CD103 + lung DC subset that excels in cross-priming revealed that these cells control the priming of naive CD8 + T cells during influenza virus infection (4) or Sendai virus infection (5). However similar to lymphoid tissue CD8 + DCs, CD103 + DCs are also very potent at direct priming of CD8 + T cells (6) (J. Helft and M. Merad, unpublished observations), suggesting the possibility that the reduced CD8 + T cell responses (4, 5) resulted from the loss of direct antigen presentation normally provided by infected CD103 + DCs. Thus the physiological contribution of cross-presentation to the induction of anti-influenza virus CD8 + T cell immunity in vivo is still a matter of deb-ate.Attempts to generate recombinant fluorescent influenza viruses have been hampered because most of the viruses expressing reporter genes have reduced levels of replication and do not show significant pathogenesis in mice (7). In this study, we visualized the route of viral antigen uptake by lung and LN DCs and examined the antigenic presentation pathway used by DCs to induce efficient CD8 + T cell immunity upon intranasal influenza virus infection.

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“…First, it has been well established for many years that the ion permeability of membranes dramatically increases at domain boundaries owing to structural defects and mismatches in the molecular packing (see CruzeiroHansson and Mouritsen, 1988 and references therein). Second, more recent work has described a defect in cross-presentation of phagocytosed antigens in cells in which lipid droplet biogenesis was impaired (Bougneres et al, 2009). Lipid pores are associated with droplet biogenesis, and it has been suggested that pore formation would be favored by lipids with a bulky head groups (Ploegh, 2007) and STxB precisely binds to such bulky head group lipids (i.e.…”

Section: Discussionmentioning

confidence: 99%

Retrograde transport is not required for cytosolic translocation of the B-subunit of Shiga toxin

García-Castillo

Tran

Bobard

et al. 2015

Journal of Cell Science

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Antigen-presenting cells have the remarkable capacity to transfer exogenous antigens to the cytosol for processing by proteasomes and subsequent presentation on major histocompatibility complex class-I (MHC-I) molecules, a process termed cross-presentation. This is the target of biomedical approaches that aim to trigger a therapeutic immune response. The receptor-binding B-subunit of Shiga toxin (STxB) has been developed as an antigen delivery tool for such immunotherapy applications. In this study, we have analyzed pathways and trafficking factors that are involved in this process. A covalent conjugate between STxB and saporin was generated to quantitatively sample the membrane translocation step to the cytosol in differentiated monocyte-derived THP-1 cells. We have found that retrograde trafficking to the Golgi complex was not required for STxBsaporin translocation to the cytosol or for STxB-dependent antigen cross-presentation. Depletion of endosomal Rab7 inhibited, and lowering membrane cholesterol levels favored STxB-saporin translocation. Interestingly, experiments with reducible and nonreducible linker-arm-STxB conjugates led to the conclusion that after translocation, STxB remains associated with the cytosolic membrane leaflet. In summary, we report new facets of the endosomal escape process bearing relevance to antigen cross-presentation.

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A Role for Lipid Bodies in the Cross-presentation of Phagocytosed Antigens by MHC Class I in Dendritic Cells

Cited by 149 publications

References 49 publications

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

Cross-presenting CD103+ dendritic cells are protected from influenza virus infection

Retrograde transport is not required for cytosolic translocation of the B-subunit of Shiga toxin

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