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Antigen presentation

Antigen presentation is the process by which antigen-presenting cells (APCs) display peptide fragments derived from proteins on their surface using major histocompatibility complex (MHC) molecules, enabling T lymphocytes to recognize and respond to foreign pathogens, infected cells, or abnormal proteins.^[1] This mechanism is central to the adaptive immune response, bridging innate and adaptive immunity by sampling the antigenic environment and activating effector T cells.^[1] Professional APCs, including dendritic cells, macrophages, and B cells, are primarily responsible for efficient presentation, though nearly all nucleated cells can present antigens via MHC class I.^[1] There are two main pathways of antigen presentation, distinguished by the source of antigens and the MHC molecules involved. The MHC class I pathway processes endogenous antigens, such as those from intracellular pathogens like viruses or cytosolic proteins from defective ribosomal products, into short peptides (typically 8–10 amino acids) that are loaded onto MHC class I molecules in the endoplasmic reticulum (ER).^[2] These peptide-MHC class I complexes are then transported to the cell surface for recognition by CD8+ cytotoxic T cells, which trigger the destruction of infected or malignant cells.^[2] Key steps include proteasomal degradation in the cytosol, peptide transport into the ER via the transporter associated with antigen processing (TAP), and assembly with MHC class I heavy chains and β2-microglobulin, facilitated by chaperones like tapasin.^[2] In contrast, the MHC class II pathway handles exogenous antigens, such as those from extracellular bacteria or engulfed pathogens, which are internalized by endocytosis, phagocytosis, or receptor-mediated uptake and degraded in acidic endosomal/lysosomal compartments by proteases like cathepsin S.^[3] Peptides (13–25 amino acids) bind to MHC class II molecules within multivesicular bodies (MVBs), where the invariant chain (Ii) is proteolytically removed and replaced via HLA-DM-mediated editing, before the complexes traffic to the plasma membrane.^[3] This presentation activates CD4+ helper T cells, which coordinate humoral immunity through B cell activation and cytokine production, as well as cellular responses.^[1] A specialized process known as cross-presentation allows exogenous antigens to be presented on MHC class I molecules, primarily by dendritic cells, to prime CD8+ T cells against threats that do not directly infect the APC, such as viruses in dying cells or tumor antigens.^[4] Two main mechanisms exist: the phagosome-to-cytosol pathway, where antigens are exported to the cytosol for proteasomal processing and TAP-dependent loading, and the vacuolar pathway, involving endosomal proteases like cathepsin S without TAP.^[4] This pathway is crucial for antitumor immunity, antiviral responses, and tolerance mechanisms, highlighting the versatility of APCs in surveilling diverse threats.^[4]

Fundamentals of Antigen Presentation

Definition and Biological Role

Antigen presentation is the cellular process by which peptide fragments derived from antigens are bound to major histocompatibility complex (MHC) molecules and displayed on the surface of antigen-presenting cells for recognition by T lymphocytes.^[5] This mechanism is fundamental to the adaptive immune system, as it allows T cells to survey cellular contents and initiate targeted responses.^[6] The biological role of antigen presentation centers on immune surveillance, enabling the distinction between self and non-self molecules to trigger adaptive immunity against intracellular and extracellular threats, including pathogens, tumor cells, and allogeneic transplants.^[7] Through this process, MHC class I molecules present peptides to cytotoxic CD8+ T cells for the elimination of infected or malignant cells, while MHC class II molecules display antigens to helper CD4+ T cells, which orchestrate broader immune activation, such as antibody production and inflammation.^[8] This dual pathway ensures comprehensive protection by linking antigen detection to effector functions.^[9] Evolutionarily, the extreme polymorphism of MHC genes has been selected to promote population-level diversity in peptide binding and presentation, thereby enhancing collective resistance to pathogen evolution and variability.^[10] This genetic diversity ensures that not all individuals are susceptible to the same infectious agents, as varying MHC alleles allow for a broader repertoire of recognizable antigens across a population.^[11] In contrast to innate immunity's generic pattern recognition, the adaptive specificity of antigen presentation derives from the precise interaction between T cell receptors and peptide-MHC complexes, fostering antigen-specific memory and long-term protection.^[12]

Antigens and MHC Molecules

Antigens are molecules capable of eliciting an immune response, typically derived from pathogens, tumors, or even self-components, and include proteins, polysaccharides, or lipids.^[13] In the context of antigen presentation, protein antigens are primarily processed into smaller peptide fragments, generally ranging from 8 to 25 amino acids in length, which are then displayed on the cell surface in association with major histocompatibility complex (MHC) molecules to enable recognition by T cells.^[14] MHC class I molecules are heterodimeric proteins expressed on the surface of nearly all nucleated cells, playing a crucial role in surveilling intracellular threats.^[15] Their structure consists of a polymorphic α chain, encoded by HLA-A, -B, or -C genes in humans, comprising three extracellular domains (α1, α2, and α3), non-covalently associated with the invariant β2-microglobulin (β2m) light chain.^[16] The α1 and α2 domains fold to form a closed peptide-binding groove with two α-helices flanking a β-sheet platform, which accommodates short peptides, typically 8-10 amino acids long, derived from intracellular proteins such as those produced by viruses or aberrant cellular processes.^[17] This binding is stabilized by interactions between the peptide's N- and C-terminal residues and specific pockets (A and F, respectively) in the groove.^[18] In contrast, MHC class II molecules are primarily expressed on professional antigen-presenting cells (APCs), including dendritic cells, macrophages, and B cells, where they facilitate the presentation of extracellular antigens to CD4+ T cells.^[7] Structurally, MHC class II comprises a polymorphic α chain (HLA-DR, -DQ, or -DP α) and a β chain, each with two extracellular domains (α1, α2 and β1, β2), where the α1 and β1 domains form an open-ended peptide-binding groove capable of accommodating longer peptides, usually 13-25 amino acids, from endocytosed sources like bacterial proteins.^[19]^[20] The groove's open ends allow peptide extension beyond the binding core, enhancing flexibility in antigen display.^[18] Non-classical MHC molecules, such as human HLA-E, HLA-F, and HLA-G, exhibit limited polymorphism and specialized functions distinct from their classical counterparts, often modulating immune responses through interactions with natural killer (NK) cells and subsets of T cells.^[21] The affinity of peptide-MHC binding is critically determined by anchor residues within the peptide that fit into specific pockets of the MHC groove, with the stability of this complex influencing the efficiency and duration of antigen presentation to T cells.^[22]^[18]

MHC Class I Pathway

Intracellular Antigen Processing

Intracellular antigen processing for MHC class I presentation primarily involves the degradation of endogenously synthesized proteins located in the cytosol, such as those produced by viral infections or tumor cells.^[23] These proteins represent the main source of antigens, as they are generated within the cell and must be broken down to generate peptides that can bind MHC class I molecules.^[2] The degradation process begins with ubiquitination of these cytosolic proteins, marking them for proteolysis by the 26S proteasome, a large multi-subunit complex that cleaves them into short peptides typically 8-20 amino acids in length.^[24] In immune-activated cells, a specialized form called the immunoproteasome replaces constitutive proteasome subunits with inducible ones, including LMP2 (β1i) and LMP7 (β5i), which are upregulated by interferon-gamma (IFN-γ).^[25] This variant enhances the production of peptides with hydrophobic C-termini preferred by MHC class I molecules, improving the efficiency of antigen presentation during infections or inflammation.^[26] The generated peptides are then actively transported from the cytosol into the endoplasmic reticulum (ER) lumen by the transporter associated with antigen processing (TAP), an ATP-binding cassette (ABC) transporter formed as a heterodimer of TAP1 and TAP2 subunits.^[27] TAP harnesses ATP hydrolysis to selectively pump peptides, showing a preference for those with hydrophobic or basic C-terminal residues that align with MHC class I binding motifs.^[28] Once in the ER, excess N-terminal residues are trimmed by endoplasmic reticulum aminopeptidases ERAP1 and ERAP2, which cooperatively refine peptide lengths to the optimal 8-10 mers suitable for stable MHC class I association.^[29] ERAP1 primarily handles sequential trimming, while ERAP2 assists in generating diverse epitopes, ensuring a broad peptidome.^[30] A significant proportion of MHC class I peptides derives from defective ribosomal products (DRiPs), which are newly synthesized but misfolded or prematurely terminated polypeptides that constitute up to 30% of total translation output and are rapidly ubiquitinated for proteasomal degradation.^[31] This mechanism allows for the timely presentation of antigens from nascent proteins, including those from rapidly replicating viruses, bypassing the need to degrade long-lived mature proteins.^[32] DRiPs thus serve as a dominant and efficient source, linking translation errors directly to immune surveillance.^[33]

Assembly and Transport to Cell Surface

In the endoplasmic reticulum (ER), the assembly of major histocompatibility complex (MHC) class I molecules into peptide-loaded complexes occurs within the peptide loading complex (PLC). This multi-protein assembly includes the MHC class I heavy chain, β₂-microglobulin (β₂m), the lectin chaperone calreticulin, the oxidoreductase ERp57, and the dedicated chaperone tapasin, which collectively stabilize the nascent MHC class I and facilitate peptide binding.^[34]31541-5) Tapasin plays a central role by bridging the transporter associated with antigen processing (TAP)—which delivers proteasome-generated peptides into the ER—with the peptide-receptive MHC class I groove, enabling iterative peptide editing to favor high-affinity ligands that confer conformational stability.^[35]^[36] Quality control mechanisms ensure that only stable MHC class I-peptide complexes proceed to the cell surface, as empty or low-affinity peptide-bound MHC class I molecules are inherently unstable, prone to dissociation of β₂m, and targeted for ER-associated degradation.^[37]^[36] Tapasin enforces this selectivity by retaining immature complexes in the PLC until optimal peptide loading occurs, thereby preventing the export of suboptimal assemblies that could trigger ER stress or immune tolerance.^[37]^[38] Upon successful peptide loading, the mature MHC class I complex dissociates from the PLC and exits the ER via COPII-coated vesicles, trafficking through the Golgi apparatus before reaching the plasma membrane.^[39]^[40] Internalized MHC class I can also recycle from endosomal compartments back to the surface, extending presentation of certain peptides.^[40] At the cell surface, the half-life of these complexes ranges from several hours to over a day, dictated primarily by peptide-MHC affinity, which influences the persistence of antigen display for T cell surveillance.^[41]^[42] Pathogens exploit vulnerabilities in this process to evade immunity; for instance, human cytomegalovirus (HCMV) encodes proteins US2–US11 that disrupt assembly by redirecting MHC class I heavy chains to lysosomal degradation or retaining them in the ER, thereby reducing surface expression.^[43]^[44]

MHC Class II Pathway

Extracellular Antigen Processing

Extracellular antigens, such as those derived from pathogens or allergens, are primarily taken up by professional antigen-presenting cells (APCs) like dendritic cells, macrophages, and B cells through mechanisms including phagocytosis, macropinocytosis, and receptor-mediated endocytosis.^[3] Phagocytosis engulfs large particles like bacteria, while macropinocytosis allows nonspecific fluid-phase uptake of soluble antigens, often regulated by Rho GTPases such as CDC42 and RAC1 in dendritic cells.^[3] Receptor-mediated uptake, for instance via Toll-like receptors (TLRs) or B cell receptors (BCRs), enhances efficiency; BCR-mediated endocytosis in B cells is approximately 1,000-fold more effective than nonspecific pathways for antigen capture.^[3] Following uptake, these antigens are trafficked through the endocytic pathway, progressing from early endosomes to late endosomes and lysosomes, where they undergo proteolytic degradation to generate peptides suitable for MHC class II binding.^[14] The acidic environment of these compartments activates lysosomal proteases, including cathepsins B, S, and D, as well as asparaginyl endopeptidase (AEP), which cleave antigens into peptides of 13–25 amino acids.^[3] Cathepsin S plays a particularly critical role in this process, especially in dendritic cells and B cells, where its activity is essential for invariant chain degradation and peptide generation, as demonstrated in cathepsin S-deficient models showing impaired MHC class II presentation.^[45] In dendritic cells, proteolysis is tightly controlled to limit over-degradation and preserve immunogenic epitopes, differing from the more extensive breakdown in macrophages.^[3] The invariant chain (Ii, also known as CD74) associates with newly synthesized MHC class II molecules in the endoplasmic reticulum (ER), preventing premature peptide binding and protecting the peptide-binding groove during transit to endosomal compartments.^[46] Ii also facilitates MHC class II transport from the ER through the Golgi to late endosomes via signals in its cytoplasmic tail, targeting the complex to MHC class II-rich vesicles (MIICs).^[3] In these compartments, Ii is sequentially degraded by proteases such as cathepsin S, leaving a fragment called class II-associated invariant chain peptide (CLIP) that occupies the MHC class II groove until removal.^[45] HLA-DM, a non-polymorphic MHC class II-like molecule, functions as a peptide exchange catalyst in the MIIC compartment, promoting the dissociation of CLIP and facilitating the binding of higher-affinity antigenic peptides to MHC class II.^[47] This editing process ensures selection of immunodominant peptides, with HLA-DM interacting transiently with MHC class II to stabilize an open conformation of the peptide-binding groove, thereby enhancing the efficiency of peptide loading.^[48] In certain APCs, HLA-DM activity is modulated by HLA-DO, which influences the pH sensitivity of peptide exchange in mildly acidic endosomal environments.^[3] Although primarily focused on extracellular antigens, macroautophagy contributes to MHC class II processing by delivering cytosolic proteins to lysosomes, where they can be degraded alongside endocytosed material for peptide generation.^[49] In professional APCs like dendritic cells and B cells, autophagosomes fuse with lysosomes to form autophagolysosomes, providing 20–30% of the MHC class II peptide repertoire from endogenous sources, thus broadening the scope of presented antigens.^[3] This pathway is particularly relevant for nuclear or long-lived proteins that are inaccessible via classical endocytosis.^[50]

Loading and Presentation Mechanisms

In the MHC class II pathway, the invariant chain (Ii) is proteolytically processed in endosomal compartments to generate the class II-associated invariant chain peptide (CLIP), which occupies the peptide-binding groove of MHC class II molecules to prevent premature peptide loading. The displacement of CLIP is facilitated by HLA-DM, a non-polymorphic MHC class II-like molecule that acts as a chaperone and catalyst for peptide exchange.^[48] HLA-DM lowers the energy barrier for CLIP dissociation by inducing conformational changes in the MHC class II-peptide complex, particularly around the P1 pocket of the binding groove, thereby enabling the loading of antigenic peptides generated in endosomal compartments.^[48]^[51] In mice, the functional analog of HLA-DM is H2-DM (also known as H2-M), which performs a similar role in catalyzing CLIP release and peptide loading.^[3] Following CLIP displacement, HLA-DM engages in peptide editing to select high-affinity peptides for stable binding to MHC class II. This process favors peptides with hydrophobic residues at the P1 position, as these anchors promote optimal interactions with the hydrophobic pockets in the MHC class II groove, enhancing complex stability.^[52] HLA-DM influences the diversity of the presented peptide repertoire by preferentially catalyzing the exchange of low-affinity peptides for higher-affinity ones, thereby shaping the immunogenic potential of the MHC class II-peptide complexes.^[53] Once loaded with peptides, MHC class II molecules traffic from the MHC class II compartments (MIIC) to the plasma membrane, often via the trans-Golgi network and recycling endosomes, while residual Ii fragments are fully degraded or recycled separately.^[54] Stable peptide-MHC class II complexes on the cell surface can be internalized through endocytosis into early endosomes, where further editing by HLA-DM may occur to refine the peptide repertoire in response to environmental cues.^[55] Compared to MHC class I-peptide complexes, which typically exhibit shorter half-lives on the surface, MHC class II-peptide complexes demonstrate greater kinetic stability at neutral pH, allowing for prolonged interactions with T cells and sustained antigen presentation.^[56] The presentation of peptide-MHC class II complexes is further supported by accessory molecules, notably the CD4 co-receptor on T cells, which binds to the membrane-proximal domains of MHC class II and stabilizes the overall T cell receptor (TCR)-peptide-MHC class II interaction, enhancing signal transduction and T cell activation.^[57]

Alternative Presentation Pathways

Cross-Presentation

Cross-presentation is the specialized process by which exogenous antigens, typically derived from extracellular sources such as pathogens or apoptotic cells, are processed and presented on major histocompatibility complex (MHC) class I molecules to CD8+ T cells, thereby bridging humoral and cellular immunity.^[58] This mechanism allows antigen-presenting cells to activate cytotoxic T lymphocytes against threats that do not directly infect the presenting cell, a concept first demonstrated in seminal experiments showing indirect priming of cytotoxic responses to minor histocompatibility antigens.^[59] The process involves two primary pathways: the cytosolic pathway (Type I), which is TAP-dependent and suitable for viral antigens, and the vacuolar pathway (Type II), which is TAP-independent and often associated with bacterial antigens. In the cytosolic pathway, antigens are exported from phagosomes to the cytosol via channels like Sec61, degraded by the proteasome, and the resulting peptides are transported back into the endoplasmic reticulum or endosomes via the transporter associated with antigen processing (TAP) for loading onto MHC class I molecules.^[58]^[60] The vacuolar pathway, in contrast, occurs entirely within endosomal compartments, where antigens are proteolyzed by cathepsins and loaded directly onto recycled MHC class I molecules without cytosolic involvement or TAP.^[58] Proteasome activity is crucial post-export in the cytosolic route, while endosomal loading in the vacuolar route avoids lysosomal degradation through mechanisms like phagosomal alkalinization.^[60] Dendritic cells (DCs), particularly the cDC1 subset (CD8+ or CD103+ in mice, BDCA-3+ in humans), are the primary cells efficient at cross-presentation, with immature DCs exhibiting high capacity at steady state due to limited phagosomal acidification and enhanced antigen export.^[58]^[60] Toll-like receptor (TLR) signaling, such as via TLR3 or TLR4, upregulates this process in early maturation stages by recruiting MHC class I to phagosomes and delaying antigen degradation, though prolonged signaling in fully mature DCs impairs efficiency.^[60] Physiologically, cross-presentation is critical for priming CD8+ T cell responses against viruses and tumors in non-infected cells, enabling effective antitumor immunity and clearance of intracellular pathogens without direct cellular infection.^[58] This pathway thus plays a pivotal role in initiating adaptive immunity to extracellular threats that would otherwise evade classical MHC class I presentation of endogenous antigens.^[59]

Non-Classical MHC Presentation

Non-classical MHC molecules, also known as MHC class Ib molecules, differ from their classical counterparts by exhibiting low polymorphism and presenting diverse antigens such as lipids, vitamins, and peptides including signal peptides to innate-like lymphocytes, thereby broadening immune surveillance to microbial and stress signals.^[21] These molecules, including the CD1 family, MR1, and HLA-E, -F, and -G, have evolved to recognize conserved pathogen motifs, facilitating rapid responses from specialized T cell subsets and natural killer (NK) cells without the extensive allelic diversity of classical MHC class I and II.^[61] Unlike classical MHC, which primarily display peptides, non-classical variants feature structural adaptations like hydrophobic grooves for lipid binding, enabling detection of bacterial envelope components or host-derived signals during infection or tolerance.^[62] The CD1 family comprises five human isoforms (CD1a-e) that present glycolipids to invariant natural killer T (iNKT) cells and other lipid-reactive T cells, with distinct trafficking pathways determining antigen specificity.^[63] Group 1 CD1 molecules (CD1a, b, c) traffic through endosomal compartments to capture microbial lipids, such as mycolic acids from Mycobacterium tuberculosis bound by CD1b, which activate protective T cell responses against bacterial pathogens.^[64] CD1d, in Group 2, presents α-galactosylceramide-like glycolipids at the cell surface to iNKT cells, bridging innate and adaptive immunity through rapid cytokine release.^[63] These isoforms exhibit limited polymorphism, allowing presentation of diverse self and foreign lipids to a semi-invariant T cell repertoire, contrasting with the peptide-focused variability of classical MHC.^[62] MR1, a monomorphic MHC-like molecule, specializes in presenting vitamin B metabolites, particularly riboflavin (vitamin B2) precursors from microbial biosynthesis, to mucosal-associated invariant T (MAIT) cells.^[65] These antigens bind within MR1's groove in a manner that stabilizes the complex for recognition by the semi-invariant MAIT TCR, enabling surveillance of riboflavin-producing bacteria and fungi in mucosal tissues.^[65] Activation of MAIT cells via MR1 presentation promotes antimicrobial defenses, including IFN-γ production, and is crucial for responses to pathogens like Mycobacterium species, where metabolite levels correlate with infection control.^[66] HLA-E, -F, and -G form a trio of non-polymorphic class Ib molecules that present short signal peptides derived from classical MHC leader sequences to CD8+ T cells and NK cells, modulating immune tolerance and cytotoxicity.^[21] HLA-E binds peptides like VMAPRTLVL from HLA-A, -B, -C, or -G leaders, interacting with the CD94/NKG2A receptor on NK cells to inhibit killing of healthy cells while permitting responses to downregulated classical MHC during viral infection.^[67] HLA-G, expressed at the fetal-maternal interface, presents similar leader peptides to promote trophoblast tolerance via ILT2/4 receptors on NK cells and T cells, suppressing alloreactivity essential for pregnancy maintenance.^[67] HLA-F, though less characterized, similarly engages NK cell receptors and may contribute to placental immunity, with all three molecules showing evolutionary conservation to prioritize conserved motifs over polymorphic diversity.^[21] Evolutionarily, non-classical MHC molecules diverged early from classical lineages, retaining low polymorphism to focus on invariant antigens like microbial lipids or vitamins, which are less variable than host peptides.^[61] This divergence, evident in mammals and beyond, supports innate-like lymphocyte activation against broad pathogen classes, enhancing host defense without the balancing selection pressures that drive classical MHC diversity.^[11] Such adaptations underscore their role in innate immunity, where presentation of bacterial glycolipids via CD1 or vitamin metabolites via MR1 elicits swift, stereotyped responses from iNKT and MAIT cells, respectively.^[62]

Antigen Presentation to Lymphocytes

T Cell Recognition and Activation

T cell recognition of antigens occurs through the interaction between the T cell receptor (TCR) and peptide-major histocompatibility complex (pMHC) complexes on antigen-presenting cells (APCs). The TCR, composed of α and β chains in most T cells, confers specificity for the presented peptide and the MHC molecule, enabling discrimination of self from non-self antigens. This binding is of low affinity but highly specific, allowing T cells to survey a vast array of pMHC complexes efficiently.^[68] Co-receptors CD4 and CD8 enhance this interaction by binding to invariant regions of MHC class II and class I molecules, respectively, thereby increasing the overall avidity of the TCR-pMHC engagement and recruiting the kinase Lck to initiate downstream signaling. CD4 is expressed on helper T cells that recognize MHC class II-presented peptides, while CD8 is on cytotoxic T cells interacting with MHC class I. This co-receptor specificity ensures lineage-appropriate responses, with CD4 promoting helper functions and CD8 enabling direct cytotoxicity.^[69]^[70] Full T cell activation requires three signals: signal 1 from TCR-pMHC binding, signal 2 from costimulatory molecules such as CD28 on the T cell interacting with B7 (CD80/CD86) on the APC, and signal 3 from cytokines like IL-12 or type I interferons. Without costimulation, T cells may enter anergy, a state of unresponsiveness. These signals culminate in the production of interleukin-2 (IL-2), autocrine proliferation, and differentiation into effector cells.^[71]^[72] Upon activation, CD8+ cytotoxic T cells release perforin and granzymes from cytotoxic granules to induce apoptosis in target cells bearing the cognate pMHC, forming pores in the target membrane to deliver granzymes that activate caspases. In contrast, CD4+ helper T cells secrete cytokines such as IFN-γ to activate macrophages for enhanced phagocytosis and intracellular killing, or provide help to B cells via CD40L-CD40 interactions and cytokines like IL-4 to promote antibody class switching and affinity maturation.^[73]^[74] Tolerance mechanisms prevent autoimmunity during antigen recognition; if costimulation is absent, T cells become anergic or undergo deletion via Fas-FasL-mediated apoptosis. Regulatory T cells (Tregs), often CD4+Foxp3+, suppress excessive responses by recognizing self-pMHC on MHC class II and secreting inhibitory cytokines like IL-10 or TGF-β, or via granzyme-mediated cytotoxicity.^[75]^[76] The sensitivity of T cell activation is amplified by the serial triggering model, where a single pMHC complex can sequentially engage and activate approximately 100-200 TCRs before dissociation, allowing effective signaling from low antigen densities (as few as 1-10 pMHC per APC). This mechanism reconciles the paradox of low-affinity TCR-pMHC binding with high sensitivity to rare antigens.^[77]

B Cell Recognition of Native Antigens

B cells recognize native antigens through their B cell receptors (BCRs), which are membrane-bound immunoglobulins that bind directly to unprocessed epitopes on soluble or cell-surface antigens without requiring major histocompatibility complex (MHC) presentation.^[78] These BCRs can engage conformational epitopes, preserving the three-dimensional structure of the antigen, or linear epitopes, allowing for high-affinity interactions that initiate B cell signaling.^[79] This direct recognition enables B cells to detect a diverse array of pathogens and foreign molecules in their intact form, distinguishing it from the peptide-MHC-dependent recognition by T cells.^[80] Upon binding, the BCR facilitates the internalization of the antigen via receptor-mediated endocytosis, directing it into endosomal compartments for processing into peptides that are loaded onto MHC class II molecules.^[81] This processed antigen is then presented on the B cell surface to CD4+ T helper cells, which provide essential signals for B cell proliferation, differentiation, and antibody production, thereby linking humoral immunity to cellular interactions.^[82] The collaboration between B cells and T cells occurs prominently in germinal centers of secondary lymphoid organs, where follicular dendritic cells trap and display native antigens on their surface to sustain BCR engagement and support iterative rounds of selection.^[83] This process drives affinity maturation, somatic hypermutation, and class-switch recombination, refining antibody responses for long-term protection.^[84] Unlike T cell activation, which mandates MHC-restricted peptide presentation, B cell recognition of native antigens does not require MHC involvement for initial binding, allowing for rapid, antigen-specific responses.^[78] While polyclonal B cell activation can occur through non-specific stimuli, effective generation of memory B cells and isotype switching typically demands T cell help to amplify and diversify the response.^[82] In special cases, T cell-independent antigens, such as bacterial polysaccharides, activate B cells through extensive BCR crosslinking due to their repetitive structures, leading to extrafollicular plasma cell differentiation and short-lived antibody production without T cell involvement.^[85] These TI responses, exemplified by type II antigens like pneumococcal polysaccharides, highlight B cells' capacity for autonomous activation against certain microbial threats, though they often yield lower-affinity antibodies compared to T-dependent pathways.^[86]

Regulation and Clinical Relevance

Molecular Regulation

Antigen presentation is tightly regulated at multiple molecular levels to ensure efficient and appropriate immune responses. Cytokines play a pivotal role in modulating the expression of key components involved in antigen processing and presentation. Interferon-gamma (IFN-γ), a pro-inflammatory cytokine, upregulates the expression of major histocompatibility complex (MHC) class I and II molecules, as well as transporter associated with antigen processing (TAP) and proteasome subunits, thereby enhancing the generation and presentation of antigenic peptides.^[87] In contrast, interleukin-10 (IL-10), an anti-inflammatory cytokine, downregulates MHC class II expression and inhibits antigen presentation by antigen-presenting cells (APCs), helping to limit excessive inflammation and prevent autoimmunity.^[88] Transcription factors serve as master regulators of MHC gene expression. For MHC class II, the class II transactivator (CIITA) acts as the primary transcriptional co-activator, binding to the MHC enhanceosome and coordinating the assembly of transcription factors to drive MHC II gene transcription in professional APCs.^[89] In MHC class I regulation, the regulatory factor X (RFX) complex and nuclear respiratory factor 1 (NRF1) contribute to constitutive and inducible expression; RFX binds to the X1 box in the MHC I promoter to facilitate basal transcription, while NRF1 supports the coordinated expression of proteasome-related genes essential for antigen processing. These factors ensure cell-type-specific and stimulus-responsive control of the antigen presentation machinery. Post-translational modifications further fine-tune MHC molecule stability, trafficking, and degradation. N-linked glycosylation on MHC class I heavy chains influences proper folding in the endoplasmic reticulum (ER) and subsequent trafficking to the cell surface, with defects in glycosylation leading to retention and reduced presentation efficiency.^[90] Ubiquitination, mediated by E3 ligases such as MARCH9, targets MHC class I for lysosomal degradation, thereby downregulating surface expression to modulate immune surveillance.^[91] Cellular context, including stress and inflammatory signals, dynamically alters antigen presentation. Inflammation promotes dendritic cell (DC) maturation through Toll-like receptor signaling, upregulating MHC II, co-stimulatory molecules, and peptide loading efficiency to enhance T cell priming.^[92] Hypoxia and ER stress, common in inflamed or tumor microenvironments, activate the IRE1/XBP1 arm of the unfolded protein response (UPR), which modulates MHC class I trafficking and peptide repertoire by altering ER homeostasis and chaperone expression.^[93] Genetic variability in MHC genes profoundly influences antigen presentation and disease susceptibility. Polymorphisms in MHC alleles affect peptide binding specificity and stability; for instance, HLA-B*27 preferentially binds peptides with arginine at the B pocket, contributing to its strong association with ankylosing spondylitis via altered self-peptide presentation and potential misfolding.^[94] Recent genome-wide association studies (GWAS) have identified additional MHC-linked variants influencing autoimmune risks, such as those near ERAP1 that fine-tune peptide trimming for HLA-B27, highlighting the polygenic regulation of presentation repertoires.^[95]

Therapeutic Implications

Aberrant antigen presentation contributes to the breakdown of self-tolerance in autoimmune diseases, such as rheumatoid arthritis (RA), where specific MHC class II alleles like HLA-DR4 predispose individuals to chronic inflammation by facilitating the presentation of self-peptides to autoreactive T cells.^[96] In RA patients carrying HLA-DR4, citrullinated self-antigens are preferentially presented, triggering pathogenic CD4+ T cell responses that drive joint destruction.^[97] Therapeutic strategies targeting this process include biologic disease-modifying antirheumatic drugs (DMARDs) that modulate T cell activation and cytokine responses to restore tolerance without broad immunosuppression.^[98] In cancer, tumors evade immune surveillance through downregulation of MHC class I molecules, reducing antigen presentation to cytotoxic CD8+ T cells and allowing unchecked proliferation.^[99] This evasion mechanism is frequently observed in many solid tumors, with downregulation reported in 20-90% of cases depending on tumor type and detection method.^[99]^[100] Genetic or epigenetic alterations in the antigen processing machinery impair peptide loading onto MHC I.^[101] Immune checkpoint inhibitors, such as anti-PD-1 antibodies, counteract this by reinvigorating exhausted T cells that recognize presented tumor antigens, leading to durable responses in melanoma and lung cancer with overall survival improvements exceeding 20% in responsive patients.^[102] Vaccines leveraging antigen presentation mimic natural pathways to prime adaptive immunity, with peptide-MHC vaccines delivering pre-processed epitopes directly to T cells for enhanced specificity.^[103] Dendritic cell therapies, such as those using ex vivo-loaded DCs, amplify cross-presentation of tumor-associated antigens on MHC I, promoting robust CD8+ T cell responses in clinical trials for glioblastoma and prostate cancer, with modest objective response rates, often around 10-15%, accompanied by survival benefits in select trials.^[104]^[105] In infectious diseases, pathogens like HIV-1 exploit antigen presentation defects by downregulating MHC class I via the Nef protein, which sequesters HLA-A and HLA-B molecules intracellularly to evade CD8+ T cell killing.^[106] Similarly, COVID-19 mRNA vaccines target the SARS-CoV-2 spike protein for processing and presentation by antigen-presenting cells, eliciting both humoral and cellular immunity; these vaccines induce spike-specific CD4+ and CD8+ T cell responses in over 90% of recipients, correlating with reduced severe disease.^[107] Organ transplantation relies on MHC matching to minimize rejection, as mismatched antigens trigger alloreactive T cell responses against presented donor peptides, substantially increasing the risk of acute rejection, with rates up to 20-30% in poorly matched cases.^[108]^[109] Recent advances in CRISPR-Cas9 editing create universal donor cells by knocking out HLA genes, reducing immunogenicity and enabling off-the-shelf transplants; preclinical studies and early-phase trials exploring HLA gene editing show promise for prolonged graft survival with reduced immunosuppression needs.^[110] Future therapeutic directions emphasize AI-driven neoantigen prediction for personalized cancer vaccines, where machine learning algorithms analyze tumor genomes to identify immunogenic MHC-bound peptides with over 90% accuracy in epitope forecasting.^[111] These tools integrate HLA typing and immunogenicity data to design mRNA vaccines targeting patient-specific mutations, showing promise in phase I trials with T cell responses in 70-80% of advanced solid tumor patients.^[112]

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