Antigen processing and presentation
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P209-211
2025-11-30
39
DCs are the most efficient antigen-presenting cell (APC) population in vivo. Through specialized mechanisms, DCs capture both exogenous and endogenous antigens, process these antigens, and present them in the context of class I and class II MHC molecules to CD8+ and CD4+ T cells, respectively (Fig. 1). DCs also present lipid antigens to T cells by CD1 molecules.
Fig1. ANTIGEN PRESENTATION PATHWAYS IN DENDRITIC CELLS. The classical pathway for MHC class I antigen presentation (left) involves degradation of endogenous antigens into peptides by the proteasome followed by transport into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). In the ER, peptides are loaded onto the newly synthesized MHC class I molecules, mediated by peptide loading complex, and further trimmed for conformational stability. Subsequently, peptide–MHC class I (pMHC-I) complexes are transported to the plasma membrane. For MHC class II antigen presentation (middle), MHC-II molecules are assembled in the ER, where they associate with the invariant chain (Ii) protein. Li-MHC-II com plex is then transported to endosomes called MHC class II compartment (MIIC). Proteases in the MIIC degrade Ii, leaving class II-associated invariant chain peptide (CLIP) intact in the MHC-II peptide-binding groove. HLA-DM catalyzes the exchange of CLIP by high-affinity antigenic peptides, which are endocytosed material (from both exogenous or endogenous sources) degraded by proteases in the MIIC. Peptide-bound MHC-II (pMHC-II) are then transported to the cell membrane. Two main pathways of cross-presentation (right) have been described that allow the presentation of exogenous antigens in association with MHC class I molecules. Antigens endocytosed or phagocytosed can be cleaved into peptides by proteases and loaded onto recycling MHC-I molecules within the same phagosome or on the cell surface (vacuolar pathway, shown in light purple). Alternatively, antigens may escape from the endosome and enter the cytosol (cytosolic pathway, shown in dark purple) to be processed via the classical MHC class I pathway. It has been suggested that elements of ER can be associated with phagosomes, allowing the transfer of antigens into the cytosol by the ER-associated degradation (ERAD) pathway and degradation by the phagosome-associated proteasome. The precise mechanisms and the locations of antigen processing in cross-presentation remain to be fully understood.
MHC Class I Antigen Presentation (Endogenous Route)
Like all nucleated cells, DCs express MHC-I molecules. Antigens bound to MHC-I molecules are typically generated endogenously within the cytosol. Such endogenous antigens can be derived from both self and non-self molecules, for example, mutated or microbial proteins, respectively. Therefore, the MHC-I antigen presentation pathway is critical for mediating immune detection of transformed or infected cells.
To bind to MHC-I molecules, antigens need to be broken down into certain lengths of peptides (commonly 8 to 11 amino acids). Antigenic peptides are initially generated by proteasome degradation and peptidase trimming in cytosol and then are translocated to the ER lumen by transporter associated with antigen processing (TAP). In the ER, a transient multi-subunit peptide loading complex (PLC) is formed, which comprises TAP, ERp57, and chaperon proteins tapa sin, calreticulin, and calnexin. Interactions between these proteins and MHC-I heavy and light chains (β2-microglobulin) facilitate the assembly of MHC-I and retain empty MHC-I in a peptide receptive state within the PLC. PLC mediates the loading of antigenic pep tides onto newly synthesized MHC-I. Tapasin promotes the binding of high-affinity peptides to MHC-I by increasing the dissociation rate of suboptimal peptides. Further enhancing the optimal peptide MHC (pMHC) binding, antigenic peptides may be further trimmed by ER aminopeptidases (ERAP1/2) to increase conformational stability. Once loaded with the optimal peptide, MHC-I molecules are stabilized and routed to the cell surface, where they can present the antigenic peptide to CD8+ T cells, inducing their cytotoxic functions.
MHC Class II Antigen Presentation (Exogenous Route)
MHC-II molecules bind to peptides that are derived from extracellular proteins and from self-proteins that are degraded in the endosomal pathway. While all nucleated cells express MHC-I, only APCs express MHC-II. Although MHC-I and MHC-II molecules are structurally similar, the peptide-binding groove of MHC-II is more open and hence accommodates longer antigenic peptides (10 to 30 amino acids). Like MHC-I, the assembly of MHC-II molecules also occurs in the ER. MHC-II in the ER associates with the invariant chain (Ii) protein, which acts as a pseudopeptide to stabilize MHC-II and targets MHC-II molecules to late endosomal compartments called MHC class II compartment (MIIC) to encounter antigenic peptides. Antigenic peptides are generated in the MIIC by proteolytic degradation enabled by the acidic pH and resident proteases called cathepsins. The same proteases also degrade the Li protein bound to MHC-II, leaving a fragment called class II-associated invariant chain peptide (CLIP) intact as CLIP is bound to the MHC-II peptide-binding groove and hence protected. The chaperone protein HLA-DM catalyzes the replacement of CLIP by the antigenic peptides that bind to MHC-II with high affinity. Antigen loading to MHC-II is further controlled by HLA-DO, another chaperone protein that pairs with HLA-DM and restricts HLA-DM activity only to acidic compartments. Peptide-bound MHC-II are then transported to the cell membrane, where they can present the antigenic peptide to cognate CD4+ T cells and induce helper T cell-mediated immunity.
Cross-Presentation
Cross-presentation is the process by which APCs present exogenous antigens on MHC class I molecules. This process is important for immune surveillance as it allows APCs, which are not transformed or infected themselves, to trigger cytotoxic immune responses or to induce cross-tolerance. DCs are considered the most efficient cross presenting cells. The cross-presentation capacity of DCs varies among subsets and is influenced by the type of antigen, the inflammatory stimuli triggering PRRs and the endocytic receptor repertoire of DCs.
DCs can acquire exogenous antigens from various sources, including apoptotic cells, necrotic cells, antibody-opsonized cells, immune complexes, heat shock proteins, exosomes, and exchange of antigen containing vesicles through dynamic synapses formed between DC subsets, and even nibbling of live cells. Mechanistically, cross presentation occurs via two major pathways, the cytosolic and the vacuolar pathways. In the cytosolic pathway, endocytosed antigens are transferred to cytosol, where they are degraded by the proteasome. These antigenic peptides then may translocate either to the ER or back to the endosomes to be loaded onto MHC-I. In the vacuolar pathway, antigens are degraded by lysosomal proteases and loaded onto recycling MHC-I in endocytic compartments. Signaling through TLRs has been reported to promote cross-presentation by inducing the accumulation of the MHC-I in the endosomes. However, the exact mechanisms and their relative contribution to cross-presentation are not yet fully understood.
An alternative mechanism for antigen presentation by DCs is cross dressing. DCs can acquire fully functional pMHC complexes from other cells via trogocytosis (transfer of cell membrane patches), exosomes (vesicles that contain cellular constituents), or tunneling nanotubes. This process is called cross-dressing and allows rapid antigen presentation without the processing of antigens. DCs can acquire both MHC-I and MHC-II molecules by this method and elicit T cell responses.
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