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Antigen processing

Antigen processing is the essential immunological mechanism by which cells degrade proteins—derived from pathogens, tumors, or self—into peptide fragments that are loaded onto major histocompatibility complex (MHC) molecules and displayed on the cell surface for scrutiny by T cells, thereby bridging innate and adaptive immunity to orchestrate targeted immune responses.^[1] This process ensures that the immune system can distinguish harmful invaders from healthy tissues, playing a pivotal role in defense against infections, cancer surveillance, and maintenance of self-tolerance.^[2] The classical antigen processing pathways are divided into two primary routes: the MHC class I pathway, which handles endogenous antigens, and the MHC class II pathway, which processes exogenous antigens. In the MHC class I pathway, intracellular proteins (such as those from viruses or mutated tumor cells) are ubiquitinated and degraded by the proteasome into peptides of 8–11 amino acids, which are then transported into the endoplasmic reticulum (ER) via the transporter associated with antigen processing (TAP).^[2] There, peptides are trimmed by ER aminopeptidases (ERAP1 and ERAP2) and loaded onto nascent MHC class I molecules within the peptide-loading complex, involving chaperones like tapasin, calreticulin, and ERp57, before the peptide–MHC complex traffics to the cell surface for presentation to CD8⁺ cytotoxic T cells.^[1] This pathway is crucial for eliminating infected or aberrant cells, with recent structural insights revealing how the loading complex ensures high-affinity peptide selection.^[1] In contrast, the MHC class II pathway targets extracellular antigens taken up by endocytosis or phagocytosis, directing them to acidic endosomal compartments where they are proteolyzed by lysosomal enzymes such as cathepsins (e.g., cathepsin S, L, and F) into peptides of 13–25 amino acids.^[2] MHC class II molecules, synthesized in the ER and protected by the invariant chain (Ii) to prevent premature peptide binding, fuse with these compartments; Ii is sequentially degraded to CLIP, which is exchanged for antigenic peptides facilitated by HLA-DM (or H2-DM in mice), with HLA-DO modulating this process in certain cells like B cells and thymic epithelium.^[1] The resulting peptide–MHC class II complexes are presented to CD4⁺ helper T cells, activating cytokine production, B cell help for antibody responses, and coordination of broader immunity against bacteria, parasites, and extracellular threats.^[2] Beyond these classical routes, specialized mechanisms like cross-presentation—where exogenous antigens are routed into the MHC class I pathway by dendritic cells—enable broader immune activation, such as in anti-viral or anti-tumor responses, while emerging research highlights peptide splicing by the proteasome and immunoproteasome variants that generate novel epitopes.^[1] Dysregulation of antigen processing contributes to autoimmune diseases, chronic infections, and immune evasion by pathogens and cancers, underscoring its therapeutic potential in vaccines and immunotherapies.^[1]

Fundamentals of Antigen Processing

Definition and Biological Significance

Antigen processing refers to the intracellular degradation of protein antigens into smaller peptide fragments that can bind to major histocompatibility complex (MHC) molecules for subsequent display on the cell surface.^[1] This process is a fundamental step in enabling T cells to recognize and respond to foreign or altered self-antigens, distinguishing it from antigen presentation, which specifically involves the loading and surface expression of these peptide-MHC complexes for T cell receptor interaction.^[1] The biological significance of antigen processing lies in its role as a bridge between innate and adaptive immunity, allowing the immune system to surveil for pathogens, tumors, and aberrant cells by facilitating T cell activation.^[1] It enables CD8+ T cells to detect and eliminate virus-infected or cancerous cells through MHC class I presentation, while CD4+ T cells coordinate broader responses via MHC class II pathways, thereby preventing widespread infection or malignancy.^[1] Additionally, by selectively generating peptides from self-proteins during thymic development, antigen processing contributes to central tolerance, deleting autoreactive T cells and mitigating the risk of autoimmunity.^[3] The concept of antigen processing emerged in the 1970s through pioneering studies on MHC restriction, where Rolf Zinkernagel and Peter Doherty demonstrated that T cell-mediated cytotoxicity requires antigens to be presented in the context of self-MHC molecules.^[4] Their work, recognized with the 1996 Nobel Prize in Physiology or Medicine, established that immune recognition is not direct but depends on processed peptides bound to MHC, laying the foundation for understanding immune surveillance against altered self-components.^[5]

MHC Molecules: Structure and Roles

Major histocompatibility complex (MHC) molecules are cell surface glycoproteins essential for antigen presentation to T lymphocytes, encoded by genes in the MHC locus on chromosome 6 in humans (known as human leukocyte antigen or HLA genes).^[6] These molecules bind peptide fragments derived from antigens and display them for recognition by T cell receptors, thereby linking innate and adaptive immunity.^[6] MHC molecules are divided into class I and class II, each with distinct structures adapted to specific antigen sources and T cell subsets.^[7] MHC class I molecules form a heterodimer consisting of a polymorphic heavy chain (α chain) non-covalently associated with the invariant light chain β2-microglobulin.^[8] The α chain comprises three extracellular domains: α1 and α2 form the peptide-binding platform, while α3 interacts with CD8 on T cells.^[8] The peptide-binding groove, located between the α1 and α2 helices atop a β-sheet platform, is closed at both ends, accommodating peptides typically 8-10 amino acids in length.^[8] This structure was first elucidated by X-ray crystallography of HLA-A2, revealing how peptides anchor via specific residues into pockets within the groove.^[8] In contrast, MHC class II molecules are heterodimers of α and β chains, both polymorphic and transmembrane, with each chain featuring two extracellular domains (α1, α2 and β1, β2). The peptide-binding groove is formed by α1 and β1 domains, with open ends allowing binding of longer peptides, usually 13-25 amino acids. The closed sides of the groove are lined by α-helices, and the floor by an antiparallel β-sheet, as determined in the crystal structure of HLA-DR1. This open-ended design permits peptide overhangs and flexibility in binding diverse sequences.^[6] MHC genes exhibit extraordinary polymorphism, with codominant expression enabling individuals to express diverse alleles from both parental haplotypes.^[7] In humans, class I loci (HLA-A, -B, -C) encode over 8,900 (HLA-A), 10,600 (HLA-B), and 8,900 (HLA-C) alleles, while class II loci (HLA-DR, -DQ, -DP) have thousands more, totaling more than 29,000 class I and 13,000 class II alleles documented as of October 2025.^[9] This variability, concentrated in the peptide-binding regions, influences binding specificity and the repertoire of presented peptides, enhancing population-level immune diversity.^[7] Functionally, MHC class I molecules present endogenous peptides to CD8+ cytotoxic T cells, triggering responses against intracellular pathogens like viruses or tumors.^[6] MHC class II molecules display exogenous peptides to CD4+ helper T cells, promoting cytokine production, B cell activation, and orchestration of immune responses.^[6] Non-classical MHC molecules, such as class Ib (e.g., HLA-E, -F, -G), present lipids, stress signals, or invariant peptides to innate-like T cells or natural killer cells, modulating tolerance and surveillance.^[10] Peptide binding to MHC molecules relies on anchor residues that fit into specificity pockets, determining affinity and complex stability on the cell surface.^[8] For class I, conserved motifs require anchors at positions 2 and the C-terminus, while class II binding involves a core 9-mer with anchors at relative positions P1, P4, P6, and P9, allowing flanking residues to extend beyond the groove. These interactions ensure selective presentation of immunogenic peptides.^[6]

Primary Processing Pathways

Endogenous Pathway for MHC Class I

The endogenous pathway for MHC class I antigen processing primarily handles intracellular proteins, such as those synthesized in the cytosol from viral infections or aberrant tumor cells, converting them into peptides for presentation to CD8+ T cells.^[2] This process ensures immune surveillance of intracellular threats by generating peptides that bind to MHC class I molecules, which are then displayed on the cell surface.^[11] Unlike other pathways, it originates in the cytosol and relies on dedicated machinery to produce peptides typically 8-10 amino acids long, optimized for MHC class I binding grooves.^[12] The pathway begins with ubiquitination of endogenous proteins in the cytosol, marking them for degradation; this step is crucial for targeting defective ribosomal products (DRiPs) and other short-lived proteins that serve as major antigen sources. These ubiquitinated proteins are then degraded by the 26S proteasome into short peptides, a process enhanced by the immunoproteasome variant, which incorporates inducible subunits LMP2 and LMP7 in response to interferon-γ (IFN-γ) to generate peptides with hydrophobic C-termini suitable for MHC class I.^[13] The resulting peptides are transported across the endoplasmic reticulum (ER) membrane via the transporter associated with antigen processing (TAP), an ATP-dependent heterodimer of TAP1 and TAP2 that selectively translocates peptides of appropriate length and sequence.^[14] In the ER, peptides undergo further trimming by aminopeptidases ERAP1 and ERAP2, which remove N-terminal residues to yield optimal 8-10 mer ligands while destroying unsuitable ones.^[15] Peptide loading onto nascent MHC class I molecules occurs within the peptide-loading complex (PLC) in the ER, involving chaperones such as calnexin for initial folding of the MHC heavy chain, followed by calreticulin and ERp57 for stabilization.^[11] Tapasin acts as a key editor in the PLC, bridging TAP to the MHC class I-β2-microglobulin complex and promoting the exchange of low-affinity peptides for high-affinity binders, ensuring only stable complexes proceed.^[16] This editing enhances peptide diversity and affinity, with tapasin-deficient cells showing reduced surface MHC class I expression.^[17] The outcome is the formation of stable MHC class I-peptide complexes that exit the ER via the secretory pathway and traffic to the plasma membrane, where they are recognized by CD8+ T cells to trigger cytotoxic responses against infected or malignant cells.^[2] This pathway is tightly regulated; for instance, IFN-γ upregulates immunoproteasome subunits and TAP to boost antigen presentation during infections.^[18] However, some tumors evade detection by downregulating TAP expression, leading to impaired peptide transport and reduced MHC class I surface levels, as observed in colorectal and breast cancers.^[19]

Exogenous Pathway for MHC Class II

The exogenous pathway processes extracellular antigens, such as those derived from bacteria or other pathogens, primarily in professional antigen-presenting cells (APCs) like dendritic cells, macrophages, and B cells. These antigens are internalized through mechanisms including receptor-mediated endocytosis, macropinocytosis, or phagocytosis, delivering them to early endosomal compartments where the acidic environment begins their maturation into late endosomes and lysosomes.^[20] Once in these vesicular compartments, antigens undergo proteolytic degradation by lysosomal proteases, notably cathepsins B, L, and S, generating peptides typically 13-25 amino acids in length suitable for binding to MHC class II molecules.^[20] This degradation is pH-dependent and optimized in the acidic milieu of multivesicular bodies (MVBs), also known as MHC class II compartments (MIIC), ensuring efficient peptide production for subsequent loading.^[20] A critical aspect of this pathway involves the invariant chain (Ii, also known as CD74), which associates with newly synthesized MHC class II αβ heterodimers in the endoplasmic reticulum (ER) to prevent premature peptide binding and stabilize the complex during transit through the Golgi apparatus.^[21] The Ii trimer fills the peptide-binding groove of MHC class II, with its CLIP (class II-associated invariant chain peptide) segment occupying the groove, while dileucine motifs in Ii's cytoplasmic tail direct the complex to endosomal compartments via clathrin-mediated endocytosis from the plasma membrane.^[20] In the MIIC, Ii is sequentially degraded by endosomal proteases; initial cleavage by cathepsins B or L removes most of the chain, leaving the CLIP fragment bound to MHC class II, and final removal of CLIP is facilitated by cathepsin S, which is essential for generating a competent peptide-binding site, particularly in B cells and dendritic cells.^[20] Peptide loading onto MHC class II is regulated by HLA-DM, a non-polymorphic MHC class II-like molecule that acts as a peptide editor in the MIIC by catalyzing the removal of CLIP and promoting the exchange for higher-affinity antigenic peptides. HLA-DM transiently interacts with MHC class II, accelerating peptide dissociation and favoring stable peptide-MHC class II complexes that resist further editing, thereby ensuring immunodominant epitopes are selected for presentation.^[20] The resulting peptide-MHC class II complexes are transported to the APC surface via vesicular tubules, where they can engage CD4+ T cells to initiate adaptive immune responses.^[20] In macrophages, efficiency of the exogenous pathway is enhanced by Fc receptor-mediated uptake of antibody-opsonized antigens, which directs immune complexes into endosomal compartments for accelerated processing and presentation, amplifying T cell activation against pathogens.^[22]

Specialized Processing Mechanisms

Cross-Presentation Pathway

Cross-presentation is a specialized antigen processing mechanism predominantly employed by dendritic cells to load exogenous antigens onto major histocompatibility complex class I (MHC class I) molecules for presentation to CD8+ T cells.^[23] This process enables the activation of cytotoxic T lymphocytes against pathogens or tumors that do not directly infect the antigen-presenting cells, thereby linking innate and adaptive immunity.^[23] The pathway was first identified in the mid-1970s through experiments demonstrating that minor histocompatibility antigens from allogeneic cells could prime CD8+ T cell responses in vivo, a phenomenon termed cross-priming. The process operates through two main routes: the vacuolar pathway and the cytosolic pathway. In the vacuolar pathway, exogenous antigens internalized via phagocytosis are degraded by lysosomal proteases, such as cathepsin S, within endosomal or phagosomal compartments, generating peptides that bind to recycling MHC class I molecules in a transporter associated with antigen processing (TAP)-independent fashion.^[24] The cytosolic pathway, in contrast, requires the translocation of antigens from phagosomes to the cytosol, where they undergo proteasomal degradation before peptides are imported via TAP into the endoplasmic reticulum (ER) or fused phagosomes for MHC class I loading.^[24] Central steps include antigen uptake through phagocytosis or endocytosis by dendritic cells, followed by pathway-specific processing. For the cytosolic route, export occurs via the Sec61 translocon, enabling proteasomal cleavage, while ER-phagosome fusion mediated by Sec22b recruits TAP and other ER machinery to non-canonical loading sites.^[24] Peptide trimming by aminopeptidases like ERAP1 or IRAP refines the epitopes before stable MHC class I-peptide complexes traffic to the cell surface.^[24] Cross-presentation plays a pivotal role in anti-viral immunity by presenting viral antigens from infected cells to CD8+ T cells and in anti-tumor responses by exposing tumor-derived antigens without necessitating dendritic cell infection.^[23] Toll-like receptor (TLR) signaling further augments this pathway by promoting phagosomal tubulation and MHC class I delivery, enhancing efficiency during early dendritic cell maturation.^[25]

Autophagy-Dependent Processing

Macroautophagy, a form of autophagy, involves the sequestration of cytosolic components, including proteins and organelles, into double-membrane-bound autophagosomes that subsequently fuse with lysosomes for degradation.^[26] In the context of MHC class II antigen processing, macroautophagy delivers long-lived cytoplasmic proteins and organelles to MHC class II compartments (MIICs) for peptide loading and presentation to CD4+ T cells.^[27] This process is particularly enhanced in thymic epithelial cells, where it facilitates the presentation of endogenous self-antigens to promote central T cell tolerance and prevent autoimmunity. For MHC class I antigen processing, autophagy contributes to the cross-presentation of intracellular antigens, such as those from viruses or tumors, by providing an alternative pathway to the conventional proteasome-dependent route.^[28] This involves the formation of phagophores at the endoplasmic reticulum (ER), which initiate autophagosome assembly and enable the delivery of cytosolic antigens for MHC class I loading.^[29] Key regulators of autophagy in antigen processing include autophagy-related (ATG) proteins, such as ATG5 and Beclin-1, which orchestrate phagophore elongation and nucleation, respectively; these pathways are induced by cellular stresses like nutrient starvation or pathogen infection.^[30] Autophagy-dependent processing plays a critical role in maintaining self-tolerance by ensuring the presentation of intracellular self-antigens, and defects in this mechanism, such as mutations in ATG16L1, are linked to autoimmune diseases like Crohn's disease, where impaired autophagy exacerbates inflammation.^[31]^[32] Studies from the 2010s have highlighted selective forms of autophagy, such as xenophagy, which specifically targets intracellular bacteria for degradation and enhances their processing for MHC presentation, thereby bolstering adaptive immune responses against infections.

Cells and Tissues Involved

Professional Antigen-Presenting Cells

Professional antigen-presenting cells (APCs) are specialized immune cells that efficiently capture, process, and present antigens to naive T cells, enabling the initiation of adaptive immune responses. These cells constitutively express high levels of major histocompatibility complex class II (MHC II) molecules and costimulatory molecules such as B7 (CD80 and CD86) and CD40, which are essential for priming T cells by providing the necessary signals for activation and proliferation.^[33] Unlike non-professional APCs, professional APCs can stimulate naive T lymphocytes without prior activation, playing a pivotal role in bridging innate and adaptive immunity.^[34] The primary types of professional APCs include dendritic cells (DCs), macrophages, and B cells. Dendritic cells are subdivided into conventional DCs (cDCs) and plasmacytoid DCs (pDCs); cDCs are highly efficient at antigen uptake through endocytosis and macropinocytosis, processing via multiple pathways, and migrating to lymphoid organs to present antigens. pDCs, while specialized in type I interferon production, also contribute to antigen presentation, particularly in viral contexts, by capturing antigens and cross-presenting them to T cells. Macrophages excel in phagocytosis of pathogens and debris, followed by antigen processing and cytokine secretion (e.g., IL-12 and TNF-α) to modulate immune responses, often at sites of infection. B cells, in contrast, utilize their B cell receptors for high-affinity uptake of soluble antigens, enabling linked recognition where the same antigen specificity is shared between B and T cells, which supports humoral immunity.^[33]^[34]^[35] In terms of processing efficiency, DCs demonstrate superior versatility, utilizing endogenous, exogenous, and cross-presentation pathways to load antigens onto both MHC class I and II molecules, while providing robust costimulation through CD80 and CD86 to ensure full T cell activation and prevent anergy. Macrophages and B cells primarily focus on MHC II presentation of exogenous antigens, with efficiency enhanced by activation signals like IFN-γ for macrophages and CD40 ligation for B cells, though they are less potent at priming naive T cells compared to DCs. Tissue distribution varies: DCs are abundant in lymphoid tissues such as lymph nodes and spleen, where they initiate responses, whereas macrophages predominate in peripheral inflamed or infected sites like tissues and mucosal surfaces. B cells are mainly found in lymphoid organs but can traffic to sites of antigen exposure.^[33]^[34]^[35]

Dendritic Cells and Langerhans Cells

Dendritic cells (DCs) are specialized antigen-presenting cells that play a pivotal role in bridging innate and adaptive immunity, particularly at barrier sites such as the skin. In their immature state, DCs efficiently capture antigens in peripheral tissues through macropinocytosis, a process involving the formation of large endocytic vesicles that allow nonspecific uptake of soluble proteins and pathogens.^[36] Upon encountering danger signals, such as pathogen-associated molecular patterns recognized by Toll-like receptors (TLRs), immature DCs undergo maturation, which involves upregulation of major histocompatibility complex class II (MHC II) molecules, costimulatory proteins, and chemokine receptor CCR7 to facilitate migration to draining lymph nodes.^[37] This maturation process enhances their antigen processing and presentation capabilities, enabling effective priming of naive T cells.^[38] DCs exhibit superior efficiency in cross-presentation, a mechanism where exogenous antigens are loaded onto MHC class I molecules to activate cytotoxic CD8+ T cells, which is particularly pronounced in certain DC subsets like conventional DC1 (cDC1).^[39] Additionally, mature DCs secrete interleukin-12 (IL-12), a cytokine that promotes the differentiation of CD4+ T helper cells toward a Th1 phenotype, thereby directing antiviral and antitumor immune responses.^[39] In the steady state, without inflammatory cues, DCs maintain a tolerogenic function by presenting self-antigens in a way that induces regulatory T cells, preventing autoimmunity at barrier tissues.^[40] Langerhans cells (LCs), a subset of DCs residing in the epidermis, were first discovered in 1868 by Paul Langerhans, who initially mistook them for nerve cells.^[41] LCs are characterized by unique Birbeck granules, tennis racket-shaped organelles involved in antigen processing, and they express langerin, a C-type lectin receptor that mediates the uptake of pathogens through recognition of glycan structures on their surfaces.^[42] This receptor facilitates the capture and internalization of skin-associated pathogens, including fungi via β-glucan binding and viruses such as HIV-1 and herpes simplex virus.^[43]^[44] In skin immunity, LCs serve as sentinels that bridge epithelial barrier tissues to adaptive responses by migrating to lymph nodes upon activation, where they present processed antigens to T cells.^[45] They play a key role in contact hypersensitivity reactions, initiating T cell-mediated inflammation against haptens and allergens penetrating the skin.^[46] Like other DCs, LCs exhibit tolerogenic properties in the steady state, promoting immune tolerance to harmless environmental antigens and commensals at the skin barrier.^[47]

Integration with Adaptive Immunity

T Cell Activation and Recognition

T cell activation begins with the recognition of peptide-major histocompatibility complex (pMHC) complexes on antigen-presenting cells (APCs) by the T cell receptor (TCR) on naïve T cells. The TCR, composed of αβ heterodimers, binds specifically to the composite surface formed by the antigenic peptide and the MHC groove, enabling discrimination between self and foreign antigens. This interaction is of low to moderate affinity, typically in the range of 1–100 μM (dissociation constant K_D ≈ 10^{-6} M), which allows for serial engagement of multiple pMHC ligands to achieve sufficient signaling duration. CD4 and CD8 coreceptors enhance this recognition: CD4 binds MHC class II to stabilize interactions with CD4+ T cells, while CD8 binds MHC class I for CD8+ T cells, both recruiting the kinase LCK to amplify downstream signals.^[48]^[49] Full T cell activation requires three integrated signals to prevent tolerance and promote effector functions. Signal 1 is delivered by TCR-pMHC engagement, initiating proximal signaling through phosphorylation of CD3 immunoreceptor tyrosine-based activation motifs (ITAMs) by LCK and ZAP-70, leading to distal pathways such as calcium mobilization and NF-κB activation. Signal 2 provides costimulation, primarily via CD28 on T cells binding B7-1 (CD80) or B7-2 (CD86) on APCs, which sustains signaling and promotes IL-2 production; absence of this signal induces anergy, a hyporesponsive state where T cells fail to proliferate or secrete cytokines upon re-encounter with antigen. Signal 3 consists of polarizing cytokines, such as IL-12 for CD8+ T cells, directing differentiation and survival; this three-signal model, conceptualized in the 1990s, ensures robust responses while avoiding autoimmunity. These signals coalesce at the immunological synapse, a structured interface at the T cell-APC contact site featuring a central supramolecular activation cluster (cSMAC) for TCR-pMHC interactions and a peripheral SMAC for adhesion molecules, facilitating sustained signaling through actin cytoskeleton reorganization.^[49]^[50]^[51] Upon activation, CD4+ helper T cells differentiate into subsets based on cytokine milieu: Th1 cells (driven by IL-12 and IFN-γ, via T-bet) produce IFN-γ to combat intracellular pathogens; Th2 cells (IL-4, via GATA3) secrete IL-4, IL-5, and IL-13 for humoral immunity against parasites; Th17 cells (TGF-β, IL-6, IL-23, via RORγt) release IL-17 and IL-22 to target extracellular bacteria and fungi; and regulatory T cells (TGF-β, IL-2, via FOXP3) suppress responses to maintain tolerance via IL-10 and TGF-β. CD8+ cytotoxic T cells, activated similarly, acquire killing capability through perforin-mediated pore formation in target cell membranes, allowing granzyme entry to induce apoptosis via caspase activation and DNA fragmentation. These outcomes integrate processed antigens from endogenous, exogenous, or cross-presentation pathways into adaptive immunity, enabling targeted elimination of infected or malignant cells.^[52]^[53]

B Cell Activation via T-B Interactions

B cells serve as antigen-presenting cells by internalizing antigens bound to their B cell receptors (BCRs), processing them through endosomal pathways, and presenting derived peptides on major histocompatibility complex class II (MHC II) molecules to CD4+ follicular helper T (Tfh) cells. This process is highly efficient due to the antigen specificity of the BCR, which facilitates selective uptake and concentration of relevant antigens, distinguishing B cells from other professional antigen-presenting cells like dendritic cells.^[35]^[54] The interaction between antigen-presenting B cells and Tfh cells occurs via a cognate T-B immunological synapse, where T cell receptors recognize the peptide-MHC II complex on the B cell surface. This recognition triggers upregulation of CD40 ligand (CD40L) on Tfh cells, which binds CD40 on B cells, delivering critical costimulatory signals that promote B cell survival, proliferation, and differentiation. Additionally, Tfh cells secrete cytokines such as interleukin-4 (IL-4) and IL-21, which synergize with CD40 signaling to drive immunoglobulin class-switch recombination from IgM to IgG, IgE, or IgA, and somatic hypermutation for affinity maturation.^[55]^[56]^[57] These T-B interactions culminate in germinal center formation within secondary lymphoid organs, where activated B cells undergo selection and maturation into high-affinity antibody-secreting plasma cells or memory B cells. The concept of linked recognition ensures that T cell help is specific to the antigen encountered by the B cell, as both cells must recognize epitopes from the same antigenic source, preventing nonspecific activation. This mechanism, first elucidated in the 1970s through studies on T cell-dependent antibody responses, is essential for humoral immunity against T-dependent antigens such as proteins, in contrast to T-independent antigens like polysaccharides that elicit weaker, primarily IgM responses without T cell involvement.^[58]^[59]^[60]

Pathogen Evasion Strategies

Viral Mechanisms of Interference

Viruses have evolved sophisticated mechanisms to interfere with antigen processing and presentation, primarily targeting the MHC class I pathway to evade cytotoxic T cell recognition. These strategies often involve viral proteins that disrupt key steps such as protein degradation, peptide transport, and MHC molecule surface expression. By inhibiting these processes, viruses like herpesviruses, adenoviruses, and retroviruses reduce the visibility of infected cells to the immune system, facilitating persistence and replication.^[61] One prominent tactic is the inhibition of the proteasome, the cellular machinery responsible for generating antigenic peptides from cytosolic proteins. The HIV-1 Tat protein interacts directly with α- and β-subunits of the 20S proteasome, thereby inhibiting its peptidase activity and impairing the production of peptides for MHC class I loading.^[62] Similarly, the Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) contains a glycine-alanine repeat domain that blocks ubiquitin-dependent proteasomal degradation, preventing the generation of EBNA1-derived peptides and thus evading CD8+ T cell responses.^[63] Viruses also target the transporter associated with antigen processing (TAP), which shuttles peptides from the cytosol to the endoplasmic reticulum (ER) for MHC class I assembly. Cytomegalovirus (CMV) encodes the US6 glycoprotein, which retains the TAP complex in the ER membrane, inhibiting peptide translocation without disrupting TAP's peptide-binding function.^[61] In a competitive manner, herpes simplex virus (HSV) ICP47 protein binds to the peptide-binding site of TAP with high affinity (Kd ≈ 50 nM), blocking the transport of viral peptides and reducing MHC class I surface presentation.^[64] Downregulation of MHC class I molecules represents another critical interference strategy, often achieved by disrupting their trafficking or stability. The adenovirus E3/19K protein binds to MHC class I heavy chains in the ER, retaining the complexes and preventing their transport to the cell surface.^[61] Likewise, the HIV-1 Nef protein promotes the internalization and lysosomal degradation of surface MHC class I via interactions with endocytic motifs, selectively sparing HLA-C to avoid NK cell activation.^[65] To counter cross-presentation, where exogenous viral antigens are processed by dendritic cells for CD8+ T cell priming, some viruses impair dendritic cell maturation. Hepatitis B virus (HBV) surface antigen (HBsAg) inhibits the maturation and antigen-presenting capacity of myeloid dendritic cells, reducing their ability to cross-present HBV antigens and initiate effective T cell responses.^[66] Recent studies on emerging viruses highlight ongoing evolutionary adaptations in these mechanisms. For instance, the SARS-CoV-2 ORF8 protein downregulates MHC class I expression by targeting the molecules for lysosomal degradation through an autophagy-dependent pathway, thereby promoting immune evasion during infection. This finding has implications for understanding viral persistence and informing vaccine strategies that restore antigen presentation.^[67]

Bacterial and Other Pathogen Tactics

Bacteria and other pathogens employ diverse strategies to evade antigen processing and presentation, thereby subverting host immune responses. One prominent mechanism involves intracellular residence within modified phagosomes that resist maturation. For instance, Mycobacterium tuberculosis persists in macrophages by inhibiting phagosome-lysosome fusion, which prevents acidification and degradation necessary for MHC class II antigen loading.^[68] This evasion is mediated by bacterial factors such as the phosphatase SapM and kinase PknG, allowing the pathogen to avoid proteolytic processing and subsequent presentation to CD4⁺ T cells.^[69] Similarly, Listeria monocytogenes, an intracellular bacterium, secretes listeriolysin O (LLO), a cholesterol-dependent cytolysin, to perforate phagosomal membranes and escape into the cytosol shortly after uptake.^[70] Once in the cytosol, L. monocytogenes utilizes ActA, a surface protein that mimics host actin-nucleating factors, to polymerize actin and facilitate cell-to-cell spread via protrusions, thereby bypassing extracellular antigen processing pathways and evading cross-presentation by professional antigen-presenting cells.^[71] Pathogens also interfere with antigen processing through secreted toxins that disrupt immune cell function and migration. Cholera toxin (CT) from Vibrio cholerae modulates dendritic cell activation, promoting the induction of regulatory T cells (Tregs) specific for bystander antigens and thereby dampening effective T cell responses to processed antigens.^[72] This effect arises from CT's ADP-ribosyltransferase activity, which elevates cAMP levels in immune cells, altering cytokine production and favoring tolerance over immunity.^[73] Pertussis toxin (PT) produced by Bordetella pertussis inhibits G protein-coupled receptor signaling, including chemokine receptors, which blocks the migration of antigen-presenting cells and T cells to sites of infection, indirectly impairing antigen delivery for processing and presentation.^[74] By disrupting chemokine gradients, PT delays the recruitment of dendritic cells capable of cross-presentation, allowing prolonged bacterial survival.^[75] Parasitic pathogens like Toxoplasma gondii target signaling pathways critical for antigen processing machinery. This protozoan inhibits IFN-γ-induced activation of STAT1α in infected cells, thereby downregulating MHC class II gene expression and antigen presentation on dendritic cells.^[76] Consequently, T. gondii blocks the induction of immunoproteasomes, specialized proteasomes that generate peptides for MHC class I presentation, reducing the efficiency of CD8⁺ T cell priming against parasitized cells.^[77]

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