Autonomous phagosomal degradation and antigen presentation in dendritic cells

Abstract

Phagocytosis plays a critical role in both innate and adaptive immunity. Phagosomal fusion with late endosomes and lysosomes enhances proteolysis, causing degradation of the phagocytic content. Increased degradation participates in both innate protection against pathogens and the production of antigenic peptides for presentation to T lymphocytes during adaptive immune responses. Specific ligands present in the phagosomal cargo influence the rate of phagosome fusion with lysosomes, thereby modulating both antigen degradation and presentation. Using a combination of cell sorting techniques and single phagosome flow cytometry-based analysis, we found that opsonization with IgG accelerates antigen degradation within individual IgG-containing phagosomes, but not in other phagosomes present in the same cell and devoid of IgG. Likewise, IgG opsonization enhances antigen presentation to CD4 + T lymphocytes only when antigen and IgG are present within the same phagosome, whereas cells containing phagosomes with either antigen or IgG alone failed to present antigen efficiently. Therefore, individual phagosomes behave autonomously, in terms of both cargo degradation and antigen presentation to CD4 + T cells. Phagosomal autonomy could serve as a basis for the intracellular discrimination between self and nonself antigens, resulting in the preferential presentation of peptides derived from opsonized, nonself antigens.

Diversification of IgG effector functions

“…Indeed, phagocytosis of IgG-coated targets through activating FcγR pathways induces enhanced endosomal maturation and efficient degradation of lysosomal contents, which translates to improved antigen processing and presentation on MHC-II molecules, inducing thereby potent T-cell responses (13,77,(80)(81)(82). Additionally, dendritic cell maturation is associated with the balanced signaling activity of activating and inhibitory Type I FcγRs.…”

“…Additionally, dendritic cell maturation is associated with the balanced signaling activity of activating and inhibitory Type I FcγRs. Without stimulation, dendritic cells express FcγRIIa and FcγRIIb and cell maturation by IgG immune complexes is restricted through the inhibitory activity of FcγRIIb (49,77,80,82,83). Genetic deletion of Fcgr2b, mAb-mediated FcγRIIb blockade or specific engagement of FcγRIIa on dendritic cells stimulates robust dendritic cell maturation and up-regulation of co-stimulatory molecule expression, leading to potent induction of T-cell responses (49,50,82,84,85).…”

“…For phagocytes and antigen-presenting cells, such as macrophages and dendritic cells, FcγR-mediated cellular activation is accompanied by the efficient internalization of the IgG-opsonized particles and their shuffling to endosomal compartments for subsequent degradation in lysosomes (13,(77)(78)(79)(80)(81). Indeed, phagocytosis of IgG-coated targets through activating FcγR pathways induces enhanced endosomal maturation and efficient degradation of lysosomal contents, which translates to improved antigen processing and presentation on MHC-II molecules, inducing thereby potent T-cell responses (13,77,(80)(81)(82).…”

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

“…Another way to increase selectivity in antigen presentation is the formation of pMHCII microdomains that are preformed within phagosomes and maintained upon arrival at the DC plasma membrane (Bosch et al 2013). Further specificity may be achieved through autonomous control by phagosomes in contributing pMHCII for presentation, meaning that antigens are preferentially presented by MHCII when originating from antigen-carrying particles that also stimulate DC-activating receptors from within that same compartment (Blander and Medzhitov 2006;Hoffmann et al 2012). This idea is supported by the observations that TLR2 (Underhill et al 1999) and TLR4 (Husebye et al 2010;Mantegazza et al 2012) can be recruited to and signal from phagosomes.…”

TLR-dependent phagosome tubulation in dendritic cells promotes phagosome cross-talk to optimize MHC-II antigen presentation

“…TLRs such as TLR2 and TLR4 are recruited to macrophage and DC phagosomes at least partly from an intracellular pool (10)(11)(12)(13), and signal autonomously from phagosomes independent of plasma membrane TLRs (11,14,15). Autonomous phagosomal signaling from TLRs or Fcγ receptors enhances the degradation of phagocytosed proteins and assembly of MHC-II with their derived peptides (14)(15)(16). Phagosomal TLR signaling has been proposed to also promote the reorganization of phagosome-derived MHC-II-enriched compartments (MIICs) to favor the delivery of MHC-II-peptide complexes to the plasma membrane (17), analogous to TLR-stimulated formation of tubules from MIICs/lysosomes (18)(19)(20) that fuse with the plasma membrane (7) and extend toward the immunologic synapse with T cells (5).…”