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Pierre Guermonprez

Publications and source records attributed to Pierre Guermonprez.

10 recordsLinked to original sources
PubMed2006

Antigen presentation by B lymphocytes: how receptor signaling directs membrane trafficking.

Antigen capture and presentation onto MHC class II molecules by B lymphocytes is mediated by their surface antigen receptor - the B-cell receptor (BCR). The BCR must therefore coordinate the transport of MHC class II- and antigen-containing vesicles for them to converge and ensure efficient processing. Recently, progress has been made in understanding which and how these vesicular transport events are molecularly linked to BCR signaling. In particular, recent studies have emphasized the key roles of membrane microdomains and the actin cytoskeleton in regulation of membrane trafficking upon BCR engagement.

Antigen Presentation↗
PubMed2006

NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells.

To initiate adaptative cytotoxic immune responses, proteolytic peptides derived from phagocytosed antigens are presented by dendritic cells (DCs) to CD8+ T lymphocytes through a process called antigen "crosspresentation." The partial degradation of antigens mediated by lysosomal proteases in an acidic environment must be tightly controlled to prevent destruction of potential peptides for T cell recognition. We now describe a specialization of the phagocytic pathway of DCs that allows a fine control of antigen processing. The NADPH oxidase NOX2 is recruited to the DC's early phagosomes and mediates the sustained production of low levels of reactive oxygen species, causing active and maintained alkalinization of the phagosomal lumen. DCs lacking NOX2 show enhanced phagosomal acidification and increased antigen degradation, resulting in impaired crosspresentation. Therefore, NOX2 plays a critical role in conferring DCs the ability to function as specialized phagocytes adapted to process antigens rather than kill pathogens.

Acid-Base Equilibrium↗
PubMed2004

Benznidazole, a drug used in Chagas' disease, ameliorates LPS-induced inflammatory response in mice.

Benznidazole (BZL) is a drug currently used for treating Chagas' disease. Given our earlier demonstration in which BZL downregulated cytokine and nitric oxide (NO) synthesis by LPS and/or IFN-gamma-stimulated murine macrophages, we have now analysed whether this compound could exert beneficial effects in a model of LPS-induced inflammation in C57BL/6 mice. The lethal model consisted of two LPS intraperitoneal injections, 200 microg each separated by 2 h, with BZL given orally at a dose of 200 mg/kg, 18 and 2 h before the first challenge and 20 and 44 hr following the second one. In this model, BZL treatment led to a significantly decreased mortality in comparison with untreated counterparts. Remaining experiments were carried out in mice given a unique LPS dose, pretreated with BZL or not, since those subjected to the lethal protocol were unsuitable for laboratory handling. Analysis of IL-1beta, IL-6, TNF-alpha, IL-12 and iNOS mRNA expression in liver samples taken at 90 min post-LPS showed a marked reduction of the two latter mRNAs in BZL-treated mice. These animals also displayed significantly decreased peaks levels of serum TNF-alpha and IL-6, accompanied by a diminished number of IL-6-producing peritoneal macrophages. Present effects may broaden the potential usefulness of BZL in situations accompanied by an excessive inflammatory response.

Animals↗
PubMed2004

Pathways for antigen cross presentation.

Dendritic cells (DCs) have the unique ability to capture cellular tissue antigens, and to present them on MHC class I molecules to antigen-specific CD8(+) T lymphocytes after migration to the draining lymph nodes. This process, called "cross presentation" can lead either to the tolerization or activation of antigen-specific CD8(+) T cells. Antigen capture is believed to occur by phagocytosis of antigen-bearing dead cells. Recent studies suggest that the antigen transferred from the phagocytosed cell to the DC during cross presentation is a proteasome substrate, rather than a proteasomal degradation product. In most cases, the formation of the peptide-MHC class I complexes in DCs requires the export of protein antigens from phagosomes to the cytosol, where they undergo proteasomal degradation. The resulting peptides are then translocated by TAP to the lumen of a cross presentation-loading compartment, for association to MHC class I under the control of chaperones and oxido-reductases. This loading compartment may be either the endoplasmic reticulum (ER) or a mix phagosome-ER compartment. MHC class I egress from the loading compartment to cell surface remains to be analyzed.

Animals↗
PubMed2004

Control of cross-presentation during dendritic cell maturation.

The initiation of most cytotoxic immune responses requires MHC class I-restricted presentation of internalized antigens to CD8(+) T lymphocytes, a process called cross-presentation. In dendritic cells (DC), the only antigen-presenting cells that activate naive T cells, cross-presentation is particularly efficient after internalization of opsonized antigens or immune complexes, which are cross-presented through a proteasome- and transporter associated with antigen processing (TAP)-dependent MHC class I antigen presentation pathway. We now show that FcgammaR-mediated cross-presentation is tightly regulated during DC maturation. Cross-presentation increases soon after activation by lipopolysaccharides, and it is then inhibited in fully mature cells. The initial induction of cross-presentation results from an increase of both antigen internalization and delivery to the cytosol, and from a slight rise in the activity of the proteasome and TAP. The subsequent block of cross-presentation in mature DC is a consequence of the selective down-modulation of antigen internalization and cytosolic delivery, while proteasome and TAP activities continue to rise. Therefore, FcgammaR-mediated cross-presentation is regulated during DC maturation by the selective control of antigen internalization and transport to the cytosol.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

ER-phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells.

Induction of cytotoxic T-cell immunity requires the phagocytosis of pathogens, virus-infected or dead tumour cells by dendritic cells. Peptides derived from phagocytosed antigens are then presented to CD8+ T lymphocytes on major histocompatibility complex (MHC) class I molecules, a process called "cross-presentation". After phagocytosis, antigens are exported into the cytosol and degraded by the proteasome. The resulting peptides are thought to be translocated into the lumen of the endoplasmic reticulum (ER) by specific transporters associated with antigen presentation (TAP), and loaded onto MHC class I molecules by a complex "loading machinery" (which includes tapasin, calreticulin and Erp57). Here we show that soon after or during formation, phagosomes fuse with the ER. After antigen export to the cytosol and degradation by the proteasome, peptides are translocated by TAP into the lumen of the same phagosomes, before loading on phagosomal MHC class I molecules. Therefore, cross-presentation in dendritic cells occurs in a specialized, self-sufficient, ER-phagosome mix compartment.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Dendritic cells are host cells for mycobacteria in vivo that trigger innate and acquired immunity.

In the present study, we investigated in vivo the infection and APC functions of dendritic cells (DC) and macrophages (Mphi) after administration of live mycobacteria to mice. Experiments were conducted with Mycobacterium bovis bacillus Calmette-Guerin (BCG) or a rBCG expressing a reporter Ag. Following infection of mice, DC and Mphi were purified and the presence of immunogenic peptide/MHC class II complexes was detected ex vivo on sorted cells, as was the secretion of IL-12 p40. We show in this study that DC is a host cell for mycobacteria, and we provide an in vivo detailed picture of the role of Mphi and DC in the mobilization of immunity during the early stages of a bacterial infection. Strikingly, BCG bacilli survive but remain stable in number in the DC leukocyte subset during the first 2 wk of infection. As Ag presentation by DC is rapidly lost, this suggests that DC may represent a hidden reservoir for mycobacteria.

Animals↗
PubMed2002

In vivo receptor-mediated delivery of a recombinant invasive bacterial toxoid to CD11c + CD8 alpha -CD11bhigh dendritic cells.

The precise contribution of mouse dendritic cells (DC) CD8 alpha +CD11blow and CD8 alpha -CD11bhigh subsets to CTL priming is not fully defined. Here we show that CyaA, the adenylate cyclase toxin of Bordetella pertussis, an invasive bacterial toxin that binds cells through CD11b/CD18 can be exploited for the targeted delivery of an exogenous peptide to the CD8 alpha -CD11bhigh subset in vivo. Antigen (Ag) genetically inserted in the N-terminal domain of mutant CyaA devoid of catalytic activity, are targeted to CD8 alpha -CD11bhigh DC by the CD11b/CD18-dependent binding of CyaA to the cell surface. Ag is then presented by MHC class I molecules of CD8 alpha -CD11bhigh DC after a TAP-dependent, cytosolic processing. As a result, CTL are primed after a single injection, bypassing requirement for adjuvant, CD4+ T cell help and CD40 signaling. Beside the interest of the CyaA vector for vaccine development, these results show that Ag presentation focused on CD8 alpha -CD11bhigh DC in vivo is sufficient for eliciting a vigorous CTL response and that CD11b/CD18 could be a suitable surface molecule for targeting Ag to DC.

Adenylate Cyclase Toxin↗
PubMed2001

Antigen presentation and T cell stimulation by dendritic cells.

Dendritic cells take up antigens in peripheral tissues, process them into proteolytic peptides, and load these peptides onto major histocompatibility complex (MHC) class I and II molecules. Dendritic cells then migrate to secondary lymphoid organs and become competent to present antigens to T lymphocytes, thus initiating antigen-specific immune responses, or immunological tolerance. Antigen presentation in dendritic cells is finely regulated: antigen uptake, intracellular transport and degradation, and the traffic of MHC molecules are different in dendritic cells as compared to other antigen-presenting cells. These specializations account for dendritic cells' unique role in the initiation of immune responses and the induction of tolerance.

Animals↗