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MHC class II

Major histocompatibility complex (MHC) class II molecules are transmembrane glycoproteins encoded by genes within the MHC on chromosome 6 in humans, primarily expressed on professional antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells.^[1] These molecules bind and present peptide fragments derived from extracellular antigens to CD4+ T helper cells, thereby initiating and coordinating adaptive immune responses against pathogens.^[2] Their expression can be upregulated by interferon-gamma (IFN-γ) in response to immune signals, enhancing antigen presentation during infection.^[1] Structurally, MHC class II molecules are heterodimers composed of non-covalently associated α and β polypeptide chains, each around 30–35 kDa, which together form a peptide-binding groove open at both ends to accommodate longer peptides (typically 13–25 amino acids).^[2] In humans, the primary isotypes are HLA-DR, HLA-DP, and HLA-DQ, encoded by the HLA-D region, with an additional β-chain gene for HLA-DR allowing potential formation of multiple DR heterodimers.^[1] These loci exhibit extreme polymorphism, with thousands of alleles for each major class II gene (as of 2024), enabling a diverse repertoire of peptide specificities across populations to broaden immune recognition.^[1]^[3] The biosynthesis of MHC class II molecules occurs in the endoplasmic reticulum (ER), where newly synthesized αβ heterodimers associate with the invariant chain (Ii, also known as CD74) to form a nonameric complex that prevents premature peptide binding and directs trafficking to specialized endosomal compartments called MHC class II compartments (MIICs).^[2] In these acidic MIICs, exogenous antigens internalized by endocytosis or phagocytosis are degraded by lysosomal proteases into peptides; the Ii is sequentially cleaved by proteases such as cathepsin S, exposing a CLIP peptide that is exchanged for antigenic peptides with the aid of the chaperone HLA-DM.^[2] The resulting peptide-MHC class II complexes are then transported to the cell surface for surveillance by CD4+ T cells, whose T cell receptors (TCRs) recognize the composite ligand to trigger cytokine production, B cell help, and macrophage activation.^[1]^[2] Deficiencies in MHC class II expression, often due to mutations in regulatory factors like CIITA, lead to severe combined immunodeficiency (SCID) by impairing CD4+ T cell development and function.^[1] Conversely, aberrant presentation of self-peptides by MHC class II molecules is implicated in autoimmune diseases such as rheumatoid arthritis and type 1 diabetes, where certain polymorphic alleles increase susceptibility.^[2] The discovery of MHC restriction in T cell recognition, elucidated by Peter Doherty and Rolf Zinkernagel in the 1970s, underscored the pivotal role of MHC molecules in immunity and earned them the 1996 Nobel Prize in Physiology or Medicine.^[1]

Structure and Composition

Overall Architecture

MHC class II molecules are heterodimers composed of non-covalently associated α and β glycoprotein chains, each spanning the plasma membrane and serving as antigen-presenting receptors on the cell surface.^[4] The α chain has an approximate molecular weight of 34 kDa, while the β chain is about 29 kDa, with differences largely due to variations in N-linked glycosylation sites.00696-7) Each chain features two extracellular domains (α1 and α2 on the α chain; β1 and β2 on the β chain), a transmembrane domain, and a short cytoplasmic tail of roughly 10-15 amino acids that facilitates intracellular interactions.^[4] The extracellular domains adopt a characteristic folded architecture where the membrane-distal α1 and β1 domains pair to form an upper platform-like sheet of antiparallel β-pleated strands topped by α-helices, creating a binding cleft for antigenic peptides.^[4] Below this, the membrane-proximal α2 and β2 domains, which belong to the immunoglobulin superfamily C1-set fold, interact via their β-sheets and loops to stabilize the overall dimer, with each domain containing an intra-chain disulfide bridge (e.g., Cys108–Cys164 in α2; Cys114–Cys159 in β2 for HLA-DR1).^[4] The heterodimer is primarily held together by extensive non-covalent interactions, including hydrogen bonds, van der Waals contacts, and hydrophobic packing between the α and β chains, particularly at the interfaces of the Ig-like domains. This structural organization is evolutionarily conserved across mammals, reflecting its essential role in adaptive immunity, with homologous αβ heterodimers identified in species from mice to primates.^[5] In humans, MHC class II expression includes three primary isoforms—HLA-DR, HLA-DP, and HLA-DQ—each encoded by distinct gene pairs but sharing the conserved dimeric scaffold and domain arrangement. The peptide-binding platform formed by the α1β1 dimer provides the foundational site for loading and presentation of exogenous peptides to CD4+ T cells.^[4]

Peptide-Binding Region

The peptide-binding region of MHC class II molecules is formed by the membrane-distal α1 and β1 domains of the αβ heterodimer, which together create a peptide-binding cleft approximately 25 Å long and 10-12 Å wide. This open-ended groove, laterally flanked by two α-helices atop an eight-stranded β-sheet platform, accommodates antigenic peptides typically ranging from 13 to 25 amino acids in length, allowing portions of the peptide to extend beyond the cleft ends.^[6]^[7] In contrast to the closed-ended groove of MHC class I molecules, which binds shorter peptides of 8-10 residues in a more rigid manner, the MHC class II cleft lacks terminal walls, enabling bound peptides to adopt a bulged or polyproline II-like extended conformation with flexibility for longer sequences.^[8] The seminal crystal structure of HLA-DR1, resolved at 2.5 Å resolution by Brown et al. in 1993, first elucidated this architecture, demonstrating how the groove's helical walls and floor interact with peptides in an extended β-strand-like arrangement, stabilized primarily by hydrogen bonds to the peptide backbone from conserved residues such as tyrosine and asparagine in the α-helices.^[7] Refinements in subsequent structures, including the 1994 HLA-DR1 complex with a 15-residue influenza hemagglutinin peptide at 2.5 Å resolution, revealed a pronounced twist in the peptide backbone and partial solvent exposure of 35% of the peptide surface, underscoring the groove's capacity for diverse peptide conformations while maintaining core register.^[9] These interactions ensure that peptides are presented in a manner accessible to T-cell receptors, with the open design facilitating binding of variably sized ligands derived from endocytosed proteins. Specificity within the groove is dictated by four primary anchor pockets—P1, P4, P6, and P9—which accommodate side chains of peptide residues at positions 1, 4, 6, and 9 of the core binding motif, respectively. These pockets, lined by polymorphic residues, secure the peptide through a combination of hydrogen bonds (often involving tyrosine, serine, and aspartic acid) to polar side chains and van der Waals contacts to hydrophobic moieties, with the P1 pocket typically favoring aromatic or large aliphatic anchors.^[10]^[11]^[12] Allelic variations, concentrated in the β1 domain, subtly reshape these pockets—for instance, altering pocket depth or hydrophobicity in HLA-DR alleles—thereby modulating groove geometry and peptide-binding affinity without disrupting the overall heterodimeric fold.^[13]

Genetic Organization

Loci and Genes

The major histocompatibility complex (MHC) class II genes in humans are situated within the MHC region on the short arm of chromosome 6 at cytogenetic band 6p21.3, encompassing approximately 0.9 megabases (Mb) of DNA.^[14] This genomic segment is densely packed with genes that encode the α and β chains of MHC class II molecules, which form heterodimers essential for antigen presentation.^[15] The classical MHC class II genes are organized into three primary subregions: HLA-DR, HLA-DQ, and HLA-DP. The HLA-DR subregion includes a single functional DRA gene encoding the α chain and multiple DRB genes (DRB1 through DRB5) encoding β chains, with DRB1 being the primary functional locus and the others varying by haplotype.^[16] The HLA-DQ subregion comprises DQA1 (α chain) and DQB1 (β chain) genes, while HLA-DP includes DPA1 (α chain) and DPB1 (β chain) genes.^[15] In addition, non-classical genes such as HLA-DM (DMA and DMB) and HLA-DO (DOA and DOB) reside in this region, supporting MHC class II function through peptide editing and modulation.^[16] Each MHC class II gene exhibits a conserved exon-intron structure, typically comprising 5 to 6 exons that encode distinct protein domains. For instance, the DRA gene contains 5 exons: exon 1 encodes the signal peptide for membrane insertion, exons 2 and 3 encode the two extracellular domains (α1 and α2) that form part of the peptide-binding groove, exon 4 encodes the transmembrane domain and the proximal cytoplasmic tail, and exon 5 encodes the distal cytoplasmic region.^[17] Similarly, DRB1 and other β chain genes, such as DQB1 and DPB1, consist of 6 exons, with the additional exon 6 completing the cytoplasmic tail to facilitate intracellular trafficking and signaling.^[18] This modular organization reflects the evolutionary conservation of domain-specific functions across α and β chains.^[18] The multiplicity of DRB loci in humans stems from ancient gene duplication events during primate evolution. Phylogenetic analyses indicate two major diversification phases in the HLA-DRB family, each involving segmental duplications followed by allelic divergence, with the ancestral DRB gene resembling modern HLA-DRB1*04 and subsequent copies giving rise to DRB3, DRB4, DRB5, and pseudogenes like DRB2, DRB6, DRB7, DRB8, and DRB9 approximately 30–50 million years ago.^[19] These duplications expanded the β chain repertoire, enhancing antigenic diversity while maintaining α chain monomorphism in the DR subregion.^[20] Comparatively, in mice, the orthologous MHC class II genes are located in the H2 complex on chromosome 17 and include the I-A (H2-Aa and H2-Ab1) and I-E (H2-Ea and H2-Eb1) loci, which encode αβ heterodimers analogous to human HLA-DP/DQ and HLA-DR, respectively.^[21] This organization preserves the fundamental α/β pairing mechanism across mammals, underscoring the evolutionary stability of MHC class II heterodimer assembly despite species-specific locus expansions.^[21]

Polymorphism

MHC class II genes exhibit extreme polymorphism, with thousands of alleles identified across their loci, contributing to the diversity of antigen presentation in the human population. As documented in the IPD-IMGT/HLA Database, there are currently 3,892 alleles for HLA-DRB1, 966 for HLA-DQA1, 2,924 for HLA-DQB1, 877 for HLA-DPA1, and 2,911 for HLA-DPB1.^[22] This high allelic variation arises primarily from single nucleotide polymorphisms and insertions/deletions, enabling a broad repertoire of peptide-binding specificities. The polymorphism is not uniformly distributed but concentrated in specific hotspots, particularly within exon 2, which encodes the β1 domain of the β-chain. These hotspots correspond to residues forming the peptide-binding pockets, allowing allelic variants to accommodate diverse pathogen-derived peptides.^[23] Alleles at MHC class II loci are expressed in a codominant manner, meaning both maternal and paternal haplotypes are transcribed and translated equally in heterozygous individuals. Each haplotype contributes a set of α and β chains that pair to form distinct MHC class II heterodimers, resulting in up to four unique molecules per cell for the major isotypes (DP, DQ, and DR), depending on the specific allelic combinations.^[15] This codominance amplifies individual immune diversity by enabling the presentation of a wider array of peptides to T cells. The standardized nomenclature for these alleles follows the HLA system, where names such as HLA-DRB1*04:01 specify the locus, allele group, protein variant, and synonymous substitutions; serotypes like DR4 group multiple alleles sharing serological epitopes.^[24] The extraordinary polymorphism of MHC class II genes is maintained by balancing selection, primarily driven by the diversity of pathogens and the resulting selective pressure on immune responsiveness. Evidence from comparative genomics and population genetics supports heterozygote advantage, where individuals carrying dissimilar alleles at a locus exhibit enhanced resistance to infections compared to homozygotes, as they can present a broader spectrum of antigens.^[25] This mechanism, evidenced by excess nonsynonymous substitutions in peptide-binding regions and deviations from neutral allele frequency expectations, underscores the evolutionary role of MHC class II variation in adaptive immunity.^[26]

Biosynthesis and Assembly

Transcriptional Regulation

The transcription of MHC class II genes is tightly regulated to ensure constitutive expression primarily in professional antigen-presenting cells (APCs) such as dendritic cells, B cells, and macrophages. This control is mediated by a conserved promoter module known as the S-X-Y element, located proximal to the transcription start site, which facilitates the assembly of an enhanceosome complex essential for basal transcription. The S (or W/Z) box binds upstream stimulatory factor or related proteins, the X1 box recruits the RFX complex (comprising RFX5, RFXAP, and RFXANK subunits), the X2 box interacts with CREB (cAMP response element-binding protein), and the Y box binds NF-Y (nuclear factor Y), a trimeric CCAAT-binding complex; these factors cooperate to position RNA polymerase II and initiate transcription.^[27] Central to this regulation is the class II transactivator (CIITA), encoded by the MHC2TA gene on chromosome 16, which acts as a non-DNA-binding coactivator and master regulator by recruiting histone acetyltransferases (HATs) like CBP and p300 to the promoter, thereby promoting chromatin remodeling and transcriptional activation. CIITA interacts synergistically with the RFX, NF-Y, and CREB factors bound to the S-X-Y module, stabilizing the enhanceosome and enhancing gene expression up to 100-fold in APCs. The MHC2TA gene utilizes four alternative promoters to generate distinct CIITA isoforms with tissue-specific roles: type I (from promoter I) predominates in dendritic cells, type II (from promoter II) is minor and hematopoietic-specific, type III (from promoter III) is dominant in B cells and other APCs driving constitutive expression (accounting for 60-80% of CIITA mRNA in these cells), and type IV (from promoter IV) mediates interferon-gamma-inducible expression in non-APCs.^[28]^[29]^[30] Upstream of the core S-X-Y promoter, multiple distal enhancer elements—identified as additional S'-X'-Y' modules (often denoted as enhancers A, B, and C in human HLA-DR loci, or Eα1, Eα2, Eα3 in murine equivalents)—extend up to 10-15 kb and amplify transcription in a cell-type-specific manner by similarly recruiting RFX and CIITA. These enhancers loop to the promoter via chromatin interactions, contributing to coordinate regulation across MHC class II genes like HLA-DRA, HLA-DRB, and invariant chain (CD74).^[31]^[32] Epigenetic modifications further fine-tune this regulation: in expressing APCs, CIITA-induced histone H3/H4 acetylation at lysine residues (e.g., H3K9ac, H3K14ac) opens chromatin at the S-X-Y module and enhancers, while active demethylation of CpG islands in the MHC2TA promoter prevents silencing. Conversely, in non-expressing cells like fibroblasts, hypermethylation of MHC2TA promoter IV and histone deacetylation by HDACs suppress transcription, ensuring restricted expression.^[33]

Endoplasmic Reticulum Assembly

The α and β chains of MHC class II molecules are synthesized as precursors on cytosolic ribosomes and undergo co-translational insertion into the endoplasmic reticulum (ER) membrane, directed by their N-terminal hydrophobic signal peptides that are cleaved upon translocation. This process ensures proper membrane orientation, with the peptide-binding domains facing the ER lumen. In the ER, individual α and β chains fold with assistance from molecular chaperones to achieve their native conformations before heterodimerization. The lectin chaperones calnexin and calreticulin bind sequentially to the monoglucosylated N-linked glycans on nascent chains, retaining them in a folding-competent state and promoting quality control.^[34] The thiol-disulfide oxidoreductase ERp57, often recruited via its association with calnexin or calreticulin, facilitates the formation and isomerization of disulfide bonds essential for stabilizing the immunoglobulin-like domains in both chains.^[34] Misfolded or unpaired chains are retained by the Hsp70 family chaperone BiP (also known as GRP78), which binds exposed hydrophobic regions to prevent aggregation and target them for ER-associated degradation if assembly fails.^[35] Properly folded αβ heterodimers rapidly associate with the invariant chain (Ii, or CD74), a type II transmembrane protein that acts as a dedicated chaperone. Three Ii molecules bind noncovalently to a preformed trimer of αβ dimers, yielding the characteristic (αβIi)₃ nonameric complex, as revealed by recent cryo-EM structures showing a symmetric, barrel-like architecture stabilized by interactions between Ii's trimerization domain, transmembrane helices, and the MHC II extracellular regions.^[36] The class II-associated invariant chain peptide (CLIP) segment of Ii occupies and blocks the peptide-binding groove of each αβ heterodimer, preventing premature binding of endogenous ER peptides or misfolded proteins during assembly.^[36] This association not only stabilizes the complex but also masks ER retention signals on unpaired chains, promoting efficient exit from the ER via COPII-coated vesicles to the Golgi apparatus. Under conditions of ER stress, such as high biosynthetic load in antigen-presenting cells, the unfolded protein response (UPR) modulates MHC class II assembly to maintain proteostasis. Activation of the IRE1α-XBP1 arm of the UPR expands ER membrane and enhances chaperone expression (including BiP), supporting increased folding capacity for MHC II-Ii complexes and preventing overload-induced retention or degradation.^[37] However, chronic ER stress can impair UPR adaptation, leading to reduced MHC class II surface expression by disrupting chaperone availability and promoting aggregation of assembly intermediates.^[37]

Intracellular Trafficking and Expression

Cell Types and Induction

MHC class II molecules are constitutively expressed on professional antigen-presenting cells (APCs), including dendritic cells (DCs), macrophages, B cells, and thymic epithelial cells, which play central roles in initiating CD4+ T cell responses.^[38] These cells maintain steady-state surface expression to facilitate antigen surveillance and presentation in lymphoid tissues.^[39] In contrast, non-professional APCs such as endothelial cells, fibroblasts, and epithelial cells do not constitutively express MHC class II but can be induced to do so primarily through interferon-gamma (IFN-γ) signaling, enabling them to participate in antigen presentation under inflammatory conditions.^[38] This induction is mediated by the class II transactivator (CIITA), which is transcriptionally activated by IFN-γ in these cell types.^[40] Expression of MHC class II is developmentally regulated in DCs, where immature DCs exhibit low surface levels that increase dramatically upon maturation triggered by Toll-like receptor (TLR) ligands or other danger signals, enhancing their capacity for T cell activation.^[41] Tissue-specific patterns show high MHC class II expression in lymphoid organs and gut-associated lymphoid tissue (GALT), where it supports localized immune responses to commensal and pathogenic antigens.^[42] Quantitative assessments indicate that DCs express approximately 10^5 to 10^6 MHC class II molecules per cell, with immature DCs displaying around 2.5 × 10^5 and mature DCs reaching higher densities to optimize antigen presentation efficiency.^[43] Emerging research highlights MHC class II expression on non-immune cells like tumor cells, where it correlates with improved patient survival and enhanced responses to immune checkpoint inhibitors in various cancers, suggesting a role in antitumor immunity beyond traditional APCs.^[44]

Trafficking to Endosomal Compartments

Following their assembly in the endoplasmic reticulum, where the invariant chain (Ii) associates with MHC class II αβ dimers to form nonameric (αβIi)₃ complexes, these structures are exported to the Golgi apparatus via COPII-coated vesicles as part of the conventional secretory pathway.^[39] The Ii plays a critical role in facilitating this ER exit by stabilizing the complexes and preventing retention through quality control mechanisms.^[45] Within the Ii cytoplasmic tail, dileucine-based sorting motifs (such as L7I8 and M16L17) interact with adaptor protein complexes to direct trafficking, although these primarily function at later sorting steps.^[46] Additionally, the Ii protects the αβ dimers from aggregation during transport by occupying the peptide-binding groove, thereby inhibiting unwanted interactions with endogenous ER polypeptides and ensuring proper folding and solubility.^[47] In the Golgi apparatus, the MHC class II-Ii complexes undergo post-translational modifications, including the trimming and maturation of N-linked glycans on both MHC class II and Ii from high-mannose to complex forms, which is essential for stability and further trafficking.^[39] The Ii cytosolic tail, particularly in the p35 isoform, becomes phosphorylated by protein kinase C (PKC), a modification that regulates the release from ER retention signals (such as RxR motifs in extended isoforms) and promotes efficient anterograde transport through the Golgi.^[48] These processed complexes then exit the trans-Golgi network (TGN), where dileucine motifs in the Ii tail mediate sorting into clathrin-coated vesicles via interactions with adaptor proteins like AP-1.^[45] From the TGN, the complexes are delivered to late endosomal compartments known as MHC class II-rich compartments (MIIC) either directly or indirectly via transient exposure at the plasma membrane.^[39] This targeting involves the Ii dileucine motifs binding to AP-3 adaptor complexes, which facilitate incorporation into vesicles destined for lysosomal-related pathways, while mannose-6-phosphate receptors contribute to the maturation of MIIC by delivering hydrolytic enzymes necessary for the compartment's function.^[49] Upon arrival in MIIC, the acidic environment (pH approximately 5), generated by vacuolar ATPases, prepares the complexes for subsequent Ii processing by activating acid-dependent proteases.^[50] In certain antigen-presenting cells like B cells, an alternative pathway predominates, where a portion of the complexes traffic directly to the plasma membrane before internalization via clathrin-mediated endocytosis to reach MIIC, allowing rapid surface expression in response to activation signals.^[51]

Recycling Mechanisms

Surface MHC class II (MHC II) complexes, often still associated with remnants of the invariant chain (Ii) such as CLIP, are internalized primarily through clathrin-mediated endocytosis. This process is directed by dileucine-based sorting motifs located in the cytoplasmic tail of Ii or, in the case of mature peptide-loaded MHC II, in the β-chain cytoplasmic domain.^[52]^[53] Following endocytosis, these complexes are trafficked back to MHC class II compartments (MIIC) or late endosomal/lysosomal structures, where they may undergo peptide exchange facilitated by HLA-DM or be targeted for degradation. The surface half-life of peptide-MHC II complexes is typically 10-20 hours, allowing for multiple rounds of recycling before lysosomal turnover.^[54]^[55] Recycling of MHC II enables antigen-presenting cells to sustain peptide presentation by capturing and loading new exogenous antigens onto existing complexes, bypassing the need for de novo MHC II biosynthesis and thereby enhancing efficiency during prolonged immune responses.^[56] In contrast to newly synthesized MHC II, which primarily load peptides in the biosynthetic pathway, recycled complexes frequently acquire higher-affinity peptides through DM-mediated editing in endosomal compartments, optimizing the immunopeptidome for stable T cell recognition.^[57] The recycling process is tightly regulated by post-translational modifications, including ubiquitination of the MHC II β-chain by the E3 ubiquitin ligase MARCH8, which promotes rapid endocytosis and lysosomal degradation to downregulate surface expression and prevent excessive antigen presentation.^[58] Recent investigations into tolerogenic dendritic cells have revealed that altered MHC II recycling dynamics contribute to immune tolerance by favoring the presentation of low-avidity peptides or limiting surface stability, as demonstrated in studies on DC plasticity and regulatory T cell induction.^[59]

Antigen Processing and Presentation

Exogenous Pathway Overview

The exogenous pathway of antigen processing enables the presentation of extracellular (exogenous) proteins by major histocompatibility complex (MHC) class II molecules to CD4+ T cells, distinguishing it from the endogenous pathway used by MHC class I for intracellular antigens.^[39] Extracellular antigens, such as those from pathogens or allergens, are primarily taken up by professional antigen-presenting cells (APCs) including dendritic cells, macrophages, and B cells through mechanisms like receptor-mediated endocytosis (e.g., via clathrin-coated vesicles) or phagocytosis, delivering them into early endosomes.^[39] This uptake is crucial for initiating adaptive immune responses, as non-professional cells rarely express sufficient MHC class II for effective presentation.^[39] Within the endosomal-lysosomal system, internalized antigens fuse with lysosomes, where the acidic environment (pH ~4.5-5.0) facilitates proteolysis by aspartic and cysteine proteases, notably cathepsins such as cathepsin S, which cleaves antigens into peptides of 13-25 amino acids suitable for MHC class II binding.^[60] This pH-dependent degradation generates a peptide repertoire that converges with MHC class II molecules in specialized late endosomal compartments known as MHC class II compartments (MIICs) or multivesicular bodies.^[39] The invariant chain (Ii, or CD74) plays a pivotal role by associating with nascent MHC class II in the endoplasmic reticulum, blocking premature peptide binding in the neutral ER environment and directing the complex through the Golgi to MIICs via specific sorting signals, ensuring selective loading of exogenous peptides. The efficiency of this pathway is modulated by factors including antigen dose, which influences the quantity of internalized material, and the activation state of APCs, where maturation signals (e.g., via Toll-like receptors) upregulate MHC class II expression and enhance endocytic capacity.^[39] Receptor-mediated targeting, such as to DEC-205 on dendritic cells, can increase presentation efficiency up to 1,000-fold compared to fluid-phase endocytosis. The exogenous pathway was elucidated in the late 1970s and early 1980s through studies using T cell hybridomas and cloned T cells, which demonstrated that APCs process phagocytosed antigens internally before presenting them to T cells.^[61]

Peptide Loading and Exchange

In the MHC class II antigen presentation pathway, the invariant chain (Ii) is proteolytically degraded within the MHC class II-containing compartment (MIIC) by lysosomal cysteine proteases, primarily cathepsin S, with contributions from cathepsins L and B, to generate a nested set of Ii fragments culminating in the class II-associated invariant chain peptide (CLIP) that occupies the peptide-binding groove.80249-6)^[62] This stepwise degradation begins with initial cleavage by cathepsin S to remove the Ii ectodomain, followed by trimming to CLIP (residues 81-104 of human Ii), which acts as a placeholder to prevent premature peptide binding and maintain MHC class II stability during intracellular transport.^[63] Cathepsin S deficiency impairs this process, leading to accumulation of Ii fragments and reduced peptide loading efficiency, underscoring its essential role in generating competent MHC class II molecules for antigen presentation.00249-6) The release of CLIP from the MHC class II groove is catalyzed by the non-classical MHC class II molecule HLA-DM, which functions as a peptide editor by facilitating the exchange of CLIP for higher-affinity antigenic peptides derived from endocytosed proteins.90061-6) HLA-DM interacts with the lateral surfaces of the MHC class II αβ heterodimer, inducing conformational changes that destabilize the CLIP-MHC class II complex and promote CLIP dissociation without itself binding stably to the peptide groove.^[64] In addition to its catalytic role, HLA-DM serves as a molecular chaperone, stabilizing empty or partially loaded MHC class II intermediates at acidic endosomal pH to prevent aggregation and ensure their availability for peptide loading.80332-5) HLA-DM-mediated peptide exchange lowers the activation energy barrier for peptide dissociation from the MHC class II groove, selectively favoring the binding of peptides with appropriate anchor residues that form stable hydrogen bonds with conserved pockets in the groove, such as P1 and P4/P6 positions in HLA-DR alleles.49503-2/fulltext) This editing process ensures that only immunogenic, high-stability peptide-MHC class II (pMHC II) complexes are formed, as HLA-DM accelerates the off-rate of low-affinity peptides while stabilizing the transition state for high-affinity ones.^[64] Structural studies reveal that HLA-DM senses peptide-MHC interactions across the entire binding cleft, promoting an open conformation that facilitates rapid exchange in the dynamic endosomal environment.^[13] The activity of HLA-DM is modulated by HLA-DO, another non-classical MHC class II molecule that acts as a negative regulator by forming a stable complex with HLA-DM, thereby inhibiting its peptide exchange function primarily in professional antigen-presenting cells like B cells and thymic epithelial cells. In B cells, HLA-DO limits HLA-DM catalysis to preserve a diverse self-peptide repertoire on surface MHC class II, preventing over-editing that could skew antigen presentation toward high-affinity ligands.00414-3) During thymic selection, HLA-DO modulates HLA-DM to influence the presentation of self-peptides, promoting positive selection of CD4+ T cells with moderate affinity for self-MHC while restricting autoreactive clones, as evidenced by altered T cell repertoires in HLA-DO-deficient models.^[65] Recent structural analyses, including cryo-EM insights into related MHC class II loading intermediates, highlight how HLA-DO mimics substrate binding to HLA-DM, competitively blocking access to classical MHC class II molecules and fine-tuning the pMHC II repertoire.^[36]^[66] The stability of resulting pMHC II surface complexes is a critical determinant of T cell activation duration and is quantitatively assessed using thermal stability assays, such as differential scanning fluorimetry (DSF), which measures the melting temperature (Tm) of pMHC II as an indicator of peptide-binding affinity. High-stability complexes, with Tm values often exceeding 80°C for immunodominant peptides, whereas less stable ones (Tm ~65–70°C) are more prone to peptide exchange or degradation.^[67] These assays confirm that HLA-DM preferentially generates long-lived pMHC II, correlating with enhanced CD4+ T cell responses in vivo.^[68]

Regulation of Function

General Regulatory Mechanisms

MHC class II (MHC II) molecules undergo several post-translational modifications that influence their assembly, trafficking, stability, and turnover. N-linked glycosylation occurs at conserved asparagine residues on the α (Asn78) and β (Asn19) chains, which is essential for proper folding in the endoplasmic reticulum and transport to endosomal compartments; disruption of these sites impairs MHC II maturation and peptide loading. Ubiquitination, mediated by E3 ligases such as MARCH1 and MARCH8, targets MHC II for lysosomal degradation, thereby regulating surface expression and antigen presentation duration in antigen-presenting cells (APCs) like dendritic cells and B cells; for instance, MARCH8 ubiquitination prevents MHC II recycling to the plasma membrane, promoting its turnover in activated dendritic cells. These modifications ensure fine-tuned control of MHC II availability for immune surveillance. Cytokines exert significant control over MHC II expression through transcriptional and post-transcriptional mechanisms. Interferon-γ (IFN-γ), primarily secreted by activated T cells and natural killer cells, potently upregulates MHC II by inducing the class II transactivator (CIITA), a master regulator that coordinates the transcription of MHC II genes via the JAK-STAT1 pathway; this induction enhances antigen presentation in professional APCs and even non-professional cells like endothelial cells. In contrast, interleukin-10 (IL-10), an anti-inflammatory cytokine produced by regulatory T cells and macrophages, downregulates MHC II surface expression by promoting the transcription of the E3 ubiquitin ligase MARCH1, which ubiquitinates MHC II αβ heterodimers for lysosomal degradation, thereby suppressing excessive T cell activation during immune resolution. Pathogens have evolved mechanisms to evade MHC II-mediated antigen presentation, often by interfering with intracellular trafficking. The HIV-1 accessory protein Nef binds to the cytoplasmic tail of MHC II, redirecting it from endosomal compartments to early endosomes for retention and degradation, which reduces surface MHC II levels and impairs CD4+ T cell recognition of infected cells. Similarly, other microbes like cytomegalovirus exploit ubiquitination pathways to destabilize MHC II complexes. Macroautophagy contributes to MHC II function by facilitating the delivery of cytosolic antigens for presentation, a process known as endogenous MHC II cross-presentation. During macroautophagy, double-membrane autophagosomes engulf cytoplasmic proteins, which fuse with MHC II-loading compartments (MIIC) where antigens are degraded by lysosomal proteases into peptides that bind MHC II; this pathway is particularly active in professional APCs and enables presentation of intracellular pathogens or tumor antigens to CD4+ T cells. Feedback from CD4+ T cells enhances APC MHC II expression and function through costimulatory interactions. Activated CD4+ T cells express CD40 ligand (CD40L), which binds CD40 on APCs, triggering signaling cascades that upregulate CIITA and increase MHC II transcription, alongside boosting costimulatory molecules like CD80 and CD86 to amplify T cell priming. MicroRNAs (miRNAs) provide an additional layer of post-transcriptional regulation for MHC II. miR-146a, induced by inflammatory signals like lipopolysaccharide, targets the JAK-STAT pathway to suppress CIITA expression, thereby reducing MHC II levels in dendritic cells and preventing overactivation during chronic inflammation.

Specific Pathways (e.g., PSD4–ARL14/ARF7–MYO1E)

The PSD4–ARL14/ARF7–MYO1E pathway represents a specialized regulatory mechanism that modulates the intracellular trafficking of MHC class II (MHC-II) molecules in antigen-presenting cells, particularly dendritic cells (DCs). PSD4 functions as a guanine nucleotide exchange factor (GEF) that activates the small GTPase ARL14 (also known as ARF7) by promoting the exchange of GDP for GTP, thereby enabling its recruitment to MHC-II-enriched compartments such as multivesicular MHC-II compartments (MIICs). Activated ARL14/ARF7 then interacts with its effector protein ARF7EP, which in turn binds the unconventional myosin motor protein MYO1E, facilitating actin cytoskeleton-dependent motility of MHC-II vesicles. This molecular cascade ensures precise endosomal dynamics, positioning MIICs appropriately within the cell to support efficient antigen processing.^[69] In immature DCs, the pathway promotes the retention of MHC-II molecules in intracellular MIICs by driving their actin-based transport away from the plasma membrane, thereby limiting surface expression and preventing premature antigen presentation. Upon DC maturation, downregulation of this pathway—often triggered by Toll-like receptor signaling—allows MHC-II vesicles to traffic toward the cell surface, enhancing peptide-MHC-II complex export and T cell activation. By optimizing MIIC positioning and dynamics, the pathway indirectly supports endosomal maturation processes, including progressive acidification (from pH ~6.5 in early endosomes to ~5 in late MIICs) and activation of acid-dependent hydrolases like cathepsins, which are essential for invariant chain (Ii) proteolysis into CLIP and subsequent peptide loading.^[70] This fine-tuning is critical for Ii degradation efficiency, as disrupted motility can impair cathepsin S-mediated cleavage steps, leading to incomplete antigen processing.^[70] The pathway was identified in the early 2010s through a genome-wide RNAi screen in human melanoma cells expressing MHC-II, which pinpointed ARL14/ARF7 and MYO1E as regulators of MHC-II trafficking, followed by biochemical validation in DCs. Subsequent studies employed yeast two-hybrid screening to confirm ARF7EP as the linker between ARL14/ARF7 and MYO1E, and phosphoinositide-binding assays revealed PSD4's recruitment to MIIC membranes via PI(4,5)P2 and PI(3,5)P2.^[71] In DCs, this pathway plays a key role during maturation, where its activity shifts from retention to export, promoting stable peptide-MHC-II surface display. Knockdown or inhibition of pathway components, such as ARL14/ARF7 or MYO1E, disrupts MHC-II vesicle motility, resulting in aberrant MIIC accumulation and reduced Ii degradation efficiency due to suboptimal cathepsin exposure. Consequently, antigen presentation to CD4+ T cells is impaired in immature DCs, with diminished T cell proliferation and cytokine production observed in co-culture assays; paradoxically, prolonged knockdown in maturing DCs enhances surface MHC-II levels, boosting CD4+ T cell activation by up to 2-fold in some models. Although human mutations in ARL14 are rare, engineered disruptions mimic these effects, underscoring the pathway's immune-specific role.^[72] Emerging pathways involving Rab GTPases provide a comparative framework for MHC-II regulation, highlighting coordinated endosomal switches distinct from the actin-focused PSD4–ARL14/ARF7–MYO1E cascade. For instance, the Rab5-to-Rab7 transition drives early-to-late endosome maturation, facilitating MHC-II and Ii trafficking to lysosome-like MIICs, while Rab9 and Rab11 mediate recycling of peptide-loaded complexes.^[73] Recent studies have shown that Rab5/Rab7 imbalances alter DM-mediated peptide editing.^[73]

Biological and Clinical Significance

Role in Adaptive Immunity

MHC class II molecules present antigenic peptides derived from exogenous pathways to CD4+ T cells, enabling recognition through the T cell receptor (TCR), which docks diagonally onto the peptide-MHC class II complex, with complementarity-determining regions (CDRs) contacting both the peptide and MHC helices.^[74] This interaction is stabilized and amplified by the CD4 co-receptor, which binds to non-polymorphic regions on the MHC class II β2 domain, recruiting Lck kinase to phosphorylate CD3 immunoreceptor tyrosine-based activation motifs (ITAMs) and initiating downstream signaling for T cell activation.^[75] The process requires co-stimulatory signals from antigen-presenting cells, such as CD80/CD86 engaging CD28, to prevent anergy and promote full effector differentiation.^[76] Upon activation, CD4+ T cells differentiate into distinct helper subsets that orchestrate adaptive immune responses. Th1 cells, driven by T-bet transcription factor and IL-12 signaling, produce interferon-γ (IFN-γ) to activate macrophages and enhance cytotoxic CD8+ T cell responses against intracellular pathogens.^[76] Th2 cells, regulated by GATA3 and IL-4, secrete IL-4, IL-5, and IL-13 to promote B cell activation and eosinophil recruitment for humoral immunity against extracellular parasites.^[76] Th17 cells, induced by RORγt under IL-6 and TGF-β influence, release IL-17 and IL-22 to drive neutrophil recruitment and inflammation at mucosal barriers against bacteria and fungi.^[76] Regulatory T cells (Tregs), characterized by Foxp3 expression, produce IL-10 and TGF-β to suppress excessive responses and maintain peripheral tolerance.^[76] MHC class II-mediated CD4+ T cell help is crucial for B cell functions, including antibody class switching from IgM to IgG isotypes, germinal center formation, and the generation of long-lived plasma cells and memory B cells.^[77] In vaccine contexts, this pathway drives protective humoral responses; for instance, MHC class II-deficient models fail to produce antigen-specific IgG or confer immunity against influenza challenge, underscoring its necessity for effective vaccination.^[77] In the thymus, MHC class II on cortical epithelial cells presents self-peptides to developing thymocytes, deleting high-affinity autoreactive CD4+ clones through negative selection to establish central self-tolerance.^[78] The quantitative impact of MHC class II is evident in deficient models, such as Aα knockout mice, where CD4+ T cell development is severely impaired, resulting in near-complete absence of mature CD4+ single-positive thymocytes and peripheral CD4+ T cells reduced to 1-2% of total lymphocytes.^[79] Evolutionarily, MHC class II polymorphism, maintained by balancing selection including heterozygote advantage, enhances the diversity of peptide presentation, allowing broader pathogen recognition and adaptive immune flexibility across populations.^[80]

Associations with Autoimmune Diseases

Certain polymorphisms in MHC class II genes, particularly within the human leukocyte antigen (HLA) region, confer significant susceptibility to autoimmune diseases by altering peptide presentation and T-cell selection. In type 1 diabetes (T1D), the HLA-DR3 and HLA-DR4 haplotypes are strongly associated with increased disease risk, with the DR3/DR4 heterozygous genotype conferring an odds ratio of approximately 16.5 compared to neutral genotypes.^[81] This elevated risk arises from enhanced presentation of autoantigens such as insulin peptides by these alleles, leading to autoreactive CD4+ T-cell activation. Additionally, the dimorphism at position 57 of the HLA-DQβ chain plays a critical role; aspartic acid (Asp) at DQβ57 is protective against T1D by stabilizing peptide-MHC complexes that favor non-autoreactive binding, whereas valine (Val) or other non-Asp residues (e.g., alanine or serine) increase susceptibility by permitting higher-affinity binding of insulin-derived peptides, thereby promoting autoreactivity.^[82]^[83] Molecular mimicry further contributes to MHC class II-mediated autoimmunity, where self-peptides resembling microbial antigens are presented, triggering cross-reactive T-cell responses against host tissues. In T1D, for instance, viral peptides from enteroviruses mimic insulin epitopes, leading to their presentation by predisposing HLA-DR4 molecules and initiating β-cell destruction.^[84] Similar mechanisms operate in other conditions, amplifying autoreactivity following infections.^[85] Defects in MHC class II expression underlie bare lymphocyte syndrome type II (BLS II), an autosomal recessive disorder caused by mutations in transcription factors such as CIITA or RFX, resulting in profound MHC class II deficiency on antigen-presenting cells. This leads to impaired CD4+ T-cell development and severe combined immunodeficiency, characterized by recurrent infections and failure to thrive, with an estimated prevalence of less than 1 in 1,000,000 individuals worldwide.^[86]^[87] BLS II highlights the essential role of MHC class II in immune tolerance, as its absence disrupts negative selection of autoreactive T cells in the thymus. Beyond T1D, MHC class II variants are implicated in other autoimmune diseases. In rheumatoid arthritis, the HLA-DRB104:01 allele, part of the shared epitope motif (a conserved sequence at positions 70–74 in the DRβ chain), increases susceptibility by facilitating presentation of arthritogenic peptides like those from citrullinated proteins, elevating disease risk by up to threefold in carriers.^[88] For multiple sclerosis, HLA-DRB115:01 is the strongest genetic risk factor, associating with an odds ratio of about 3.0 by enhancing presentation of myelin-derived peptides to autoreactive T cells, thereby promoting central nervous system inflammation.^[89] Therapeutically, HLA typing enables risk stratification in T1D, identifying high-risk individuals (e.g., those with DR3/DR4 haplotypes) for early screening and intervention, such as immunomodulatory therapies to preserve β-cell function.^[90] Emerging strategies target peptide loading modulators like HLA-DM to alter MHC class II repertoires, potentially reducing autoreactive peptide presentation in susceptible genotypes.^[66] Recent genome-wide association studies (GWAS) post-2020 have expanded these insights, confirming MHC class II loci while identifying non-HLA modifiers that interact with HLA risk haplotypes to fine-tune autoimmune susceptibility.^[91]

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While DR3, DR4, and the DR3/DR4 genotype are the most commonly recognized HLA risk factors for T1D, many other alleles, haplotypes, and genotypes have been ...Introduction · HLA allele, haplotype, and... · Challenges and requirements...
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Autoimmune disease: genetic susceptibility, environmental triggers ...
Aug 7, 2025 · Genome-wide association studies (GWAS) have identified hundreds of risk loci, most notably within the major histocompatibility complex (MHC), ...