Simultaneous presentation and cross‐presentation of immune‐stimulating complex‐associated cognate antigen by antigen‐specific B cells

Robson, Neil C.; Donachie, Anne M.; Mowat, Allan McI

doi:10.1002/eji.200737758

Cited by 38 publications

(31 citation statements)

References 29 publications

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“…Fc␥RIIA might also be differently engaged by insoluble versus sICs. Although signaling is essential for phagocytosis itself (39), it may also play a role in subsequent events required for efficient cross-presentation, as recently reported for B cells (40). The IgG abundance in pICs (Fig.…”

Section: Discussionsupporting

confidence: 54%

Receptor-mediated phagocytosis elicits cross-presentation in nonprofessional antigen-presenting cells

Giodini

Rahner

Cresswell

2009

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

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In cross-presentation by dendritic cells (DCs), internalized proteins are retrotranslocated into the cytosol, degraded by the proteasome, and the generated antigenic peptides bind to MHC class I molecules for presentation on the cell surface. Endoplasmic reticulum (ER) contribution to phagosomal membranes is thought to provide antigen access to the ER-associated degradation (ERAD) machinery, allowing cytosolic dislocation. Because the ERAD pathway is present in all cell types and exogenous antigens encounter an ER-containing compartment during phagocytosis, we postulated that forcing phagocytosis in cell types other than DCs would render them competent for cross-presentation. Indeed, FcR␥IIA expression endowed 293T cells with the capacity for both phagocytosis and ERAD-mediated crosspresentation of an antigen provided as an immune complex. The acquisition of this ability by nonprofessional antigen-presenting cells suggests that a function potentially available in all cell types has been adapted by DCs for presentation of exogenous antigens by MHC class I molecules. C ross-presentation refers to the binding of peptides derived from exogenous proteins by MHC class I molecules and their subsequent recognition by CD8 ϩ T cells (1). The process generally requires access of the exogenous antigen to the cytosol, and, like conventional MHC class I presentation, proteasomal activity (2). Resulting peptides are then translocated from the cytosol into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP) for subsequent binding to MHC class I molecules (3).Dendritic cells (DCs) have been considered specialized antigenpresenting cells (APCs) for cross-presentation because they efficiently capture exogenous antigens and tightly regulate the pH and proteolytic activity of the endocytic pathway to minimize protein degradation (4-6). It has also been proposed that contribution of ER membrane to DC phagosomes allows exogenous antigens to access the ER-associated degradation (ERAD) machinery, normally used to dispose of misfolded proteins from the ER (7). Indeed, we showed that cross-presentation by DCs requires ERADmediated cytosolic translocation (8). Because all cell types are capable of ER quality control and use the ERAD pathway, we hypothesized that facilitating phagocytosis in nonprofessional APCs might promote ER recruitment to phagosomal membranes, rendering such cells competent for cross-presentation. Here, we show that expression of the Fc receptor Fc␥RIIA in the human 293T kidney cell line resulted in uptake of antibody-coated exogenous particles, ER contribution to phagosomes, and ERADmediated cross-presentation. Results 293T Cells Expressing Fc␥RIIA Efficiently Internalize Antibody-CoatedParticles. We generated 293T cells stably expressing an EGFPtagged version of human Fc␥RIIA (293T FcR-EGFP) (Fig. 1A) (9). Efficient internalization of antibody-coated particles by Fc␥R-expressing cells that are normally nonphagocytic has been described (10, 11), and confocal microscopy clearly sh...

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Section: Discussionsupporting

confidence: 54%

Receptor-mediated phagocytosis elicits cross-presentation in nonprofessional antigen-presenting cells

Giodini

Rahner

Cresswell

2009

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

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“…We have therefore evaluated the processing and cross-presentation of 2 human tumor antigens by different DC populations, delivered in conjunction with ISCOMATRIX adjuvant, which is known to facilitate crosspresentation of protein antigens. 4,40,41 ISCOMATRIX adjuvant composes 40nM cage-like particles, which can be mixed with antigen or into which hydrophobic antigens can be physically incorporated ("formulated"). We have previously shown that ISCOMATRIX adjuvant dramatically affects antigen processing and presentation, 4,38 and this study was undertaken to more deeply assess the capacity of ISCOMATRIX adjuvant to facilitate the cross-presentation of multiple tumor antigen-derived CTL epitopes.…”

Section: Discussionmentioning

confidence: 99%

Processing and cross-presentation of individual HLA-A, -B, or -C epitopes from NY-ESO-1 or an HLA-A epitope for Melan-A differ according to the mode of antigen delivery

Robson

McAlpine

Knights

et al. 2010

Blood

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The ability of dendritic cells (DCs) to cross-present protein tumor antigens to cytotoxic T lymphocytes (CTLs) underpins the success of therapeutic cancer vaccines. We studied cross-presentation of the cancer/testis antigen, NY-ESO-1, and the melanoma differentiation antigen, Melan-A by human DC subsets. Monocyte-derived DCs (MoDCs) efficiently cross-presented human leukocyte associated (HLA)–A2-restricted epitopes from either a formulated NY-ESO-1/ISCOMATRIX vaccine or when either antigen was mixed with ISCOMATRIX adjuvant. HLA-A2 epitope generation required endosomal acidification and was proteasome-independent for NY-ESO-1 and proteasome-dependent for Melan-A. Both MoDCs and CD1c+ blood DCs cross-presented NY-ESO-1–specific HLA-A2157-165–, HLA-B760-72–, and HLA-Cw392-100–restricted epitopes when formulated as an NY-ESO-1/ISCOMATRIX vaccine, but this was limited when NY-ESO-1 and ISCOMATRIX adjuvant were added separately to the DC cultures. Finally, cross-presentation of NY-ESO-1157-165/HLA-A2, NY-ESO-160-72/HLA-B7, and NY-ESO-192-100/HLA-Cw3 epitopes was proteasome-dependent when formulated as immune complexes (ICs) but only proteasome-dependent for NY-ESO-160-72/HLA-B7–restricted cross-presentation facilitated by ISCOMATRIX adjuvant. We demonstrate, for the first time, proteasome-dependent and independent cross-presentation of HLA-A–, B–, and C–restricted epitopes within the same full-length tumor antigen by human DCs. Our findings identify important differences in the capacities of human DC subsets to cross-present clinically relevant, full-length tumor antigens and how vaccine formulation impacts CTL responses in vivo.

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“…After binding to the BCR B lymphocytes internalize antigen and the internalized antigens are subsequently processed and presented in the context of major histocompatibility complex (MHC) class II as well as cross-presented through MHC class I. 4 Activated B cells can prime both CD4 ϩ and CD8 ϩ T cells in vivo 3,5 and antigen presentation by B cells is important in determining the level of T-cell responses. This was revealed by experiments with mice that lack MHC class II specifically on B cells but not on dendritic cells (DCs), which were characterized by impaired expansion and differentiation of T cells after immunization.…”

Section: B-cell Functions In Health and Diseasementioning

confidence: 99%

The role of B cells in the pathogenesis of graft-versus-host disease

Shimabukuro‐Vornhagen

Hallek

Storb

et al. 2009

Blood

239

194

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IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is an established, potentially curative treatment modality for malignant and nonmalignant hematologic diseases. Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic HSCT and limits its wider use. Traditionally, GVHD has been divided into 2 forms, acute and chronic, based on the time of its onset. Acute GVHD has been defined as disease occurring in the first 100 days after transplantation, whereas chronic GVHD occurs after day 100. This arbitrary distinction based on the time of onset fails to reflect the different pathophysiologic mechanisms and clinical manifestations of acute and chronic GVHD, however. Acute GVHD can occur after day 100 in patients who received a nonmyeloablative conditioning regimen or donor lymphocyte infusions. In addition, GVHD with typical clinical features of chronic GVHD can develop well before day 100 and concurrent with acute GVHD. Therefore, the National Institutes of Health consensus development project has defined new criteria for the diagnosis, staging, and response assessment of chronic GVHD. 1,2 Only a few effective therapies are currently available for the treatment of both forms of GVHD. The established immunosuppressive agents are mostly nonspecific and unfortunately associated with severe side effects, in particular the susceptibility to lifethreatening infections. Therefore, novel more selective agents are urgently needed.GVHD is an immune-mediated disease that results from a complex interaction between donor and recipient adaptive immunity. Donor-derived CD4 ϩ and CD8 ϩ T lymphocytes have classically been considered to be the main effector cells mediating GVHD pathogenesis. In fact, removal of T cells from transplant inocula almost completely prevents GVHD from developing, however, at the price of increased incidences of graft rejection and disease recurrence. In recent years, basic and clinical research has provided a more detailed mechanistic understanding of the molecules and cell types involved in the biology of the graft-versushost reaction.Because acute GVHD is thought to be mediated mainly by donor T cells, preventive and therapeutic treatment strategies have focused primarily on the inhibition of T-cell function. Recent animal studies suggest that B cells might also play an important role in the biology of GVHD. Further circumstantial evidence for the involvement of B cells in GVHD pathogenesis comes from reports of successful treatment of GVHD with B-cell depletion. The mechanisms by which B cells contribute to acute and chronic GVHD currently are only incompletely understood. Here, we provide an overview of the experimental and clinical evidence for a pathogenic role of B cells in GVHD and evaluate the implications with regard to B cell-targeted therapies for the treatment of GVHD. We conclude by providing an outlook on novel B cell-specific approaches that might prove beneficial for the treatment of GVHD. B-cell functions in health and diseaseB cells ar...

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Simultaneous presentation and cross‐presentation of immune‐stimulating complex‐associated cognate antigen by antigen‐specific B cells

Abstract: We demonstrate that uptake of oligomeric cognate antigen (OVA-hen egg lysozyme, OVA-HEL) alone or incorporated in immune-stimulating complexes (ISCOMS) facilitates presentation and simultaneous cross-presentation of OVA by HEL-specific B cells in vitro.

Cited by 38 publications

References 29 publications

Receptor-mediated phagocytosis elicits cross-presentation in nonprofessional antigen-presenting cells

Receptor-mediated phagocytosis elicits cross-presentation in nonprofessional antigen-presenting cells

Processing and cross-presentation of individual HLA-A, -B, or -C epitopes from NY-ESO-1 or an HLA-A epitope for Melan-A differ according to the mode of antigen delivery

The role of B cells in the pathogenesis of graft-versus-host disease

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