MHC Class I, Class II, Antigen Processing, And Presentation

Major histocompatibility complex (MHC) is a group of genes that encode proteins that play a crucial role in the immune system. MHC proteins are divided into two main classes: MHC class I and MHC class II.

MHC class I molecules are one of the primary ways that the immune system recognizes and eliminates cells that are infected by viruses, bacteria, or other intracellular pathogens. They are also involved in tumor surveillance, transplantation rejection, and autoimmune diseases.

MHC class I molecules are expressed on the surface of almost all nucleated cells in the body, as well as platelets. They consist of two polypeptide chains: an alpha (α) chain and a beta-2-microglobulin (β2M) chain. The α chain is encoded by one of the three highly polymorphic genes: HLA-A, HLA-B, or HLA-C in humans. The β2M chain is encoded by a non-polymorphic gene on a different chromosome. The two chains are linked non-covalently by interactions between the α3 domain of the α chain and β2M.

The α chain of MHC class I molecules has three extracellular domains: α1, α2, and α3. The α1 and α2 domains form a peptide-binding groove that can accommodate peptides of 8 to 11 amino acids in length. These peptides are derived from the degradation of cytosolic proteins by the proteasome, a complex of proteolytic enzymes. The peptides are then transported from the cytosol to the endoplasmic reticulum (ER) by a transporter protein called TAP (transporter associated with antigen processing). In the ER, the peptides bind to newly synthesized MHC class I molecules with the help of chaperone proteins such as calnexin, calreticulin, tapasin, and ERp57. The peptide-MHC class I complex then exits the ER and travels to the cell surface via the Golgi apparatus.

The peptide-binding groove of MHC class I molecules is highly variable among different alleles, which allows them to present a diverse range of peptides to the immune system. The peptides bound by MHC class I molecules are recognized by cytotoxic T cells (CTLs), which express a receptor called TCR (T cell receptor) and a co-receptor called CD8. The TCR binds to the peptide-MHC class I complex, while CD8 binds to the α3 domain of the MHC class I molecule. This interaction triggers the activation and proliferation of CTLs, which then kill the target cell by releasing perforin and granzymes, or by inducing apoptosis through Fas-FasL interaction.

MHC class I molecules can also present peptides derived from exogenous antigens, such as those taken up by phagocytosis or endocytosis. This process is called cross-presentation and it allows the immune system to detect and eliminate cells that harbor extracellular pathogens or foreign particles. Cross-presentation can occur through different mechanisms, such as phagosome-to-cytosol transport, ER-phagosome fusion, or autophagy.

MHC class I molecules can also serve as ligands for natural killer (NK) cells, which are innate immune cells that can kill infected or abnormal cells without prior sensitization. NK cells express receptors that can either activate or inhibit their cytotoxic function depending on the presence or absence of MHC class I molecules on the target cell. Some of these receptors are called KIRs (killer cell immunoglobulin-like receptors) and they recognize specific alleles of HLA-A, HLA-B, or HLA-C. Other receptors are called NKG2A/C/E and they recognize HLA-E, which is a non-classical MHC class I molecule that presents peptides derived from other MHC class I molecules. NK cells use a balance between activating and inhibitory signals to determine whether to kill or spare a target cell.

In summary, MHC class I molecules are essential for presenting intracellular antigens to CTLs and for regulating NK cell activity. They are highly polymorphic and diverse, which enables them to cope with a variety of pathogens and foreign substances. They are also involved in many clinical scenarios, such as viral infections, cancer immunotherapy, organ transplantation, and autoimmune diseases.

MHC Class I molecules are one of the main types of molecules that present antigenic peptides to the immune system. They are found on the surface of almost all nucleated cells in the body, except for some cells in the retina and brain. Their main function is to display peptides derived from proteins that are synthesized or degraded inside the cell, such as viral, bacterial, tumor, or self-proteins. These peptides are recognized by cytotoxic T cells (CTLs), which can then kill the infected or abnormal cells. This process is called the cytosolic or endogenous pathway of antigen presentation.

MHC Class I molecules are composed of two polypeptide chains: a larger alpha (α) chain and a smaller beta-2-microglobulin (β2M) chain. The α chain is encoded by one of three genes: HLA-A, HLA-B, or HLA-C in humans. These genes are highly polymorphic, meaning that there are many different variants (alleles) of each gene in the population. This diversity allows MHC Class I molecules to bind and present a wide range of peptides to CTLs. The β2M chain is encoded by a non-polymorphic gene that is not part of the MHC complex. It is essential for the stability and expression of the α chain.

The α chain of MHC Class I molecules can be divided into four domains: the peptide-binding domain, the immunoglobulin-like domain, the transmembrane domain, and the cytoplasmic domain. The peptide-binding domain is the most variable part of the molecule and contains a groove that can accommodate peptides of 8 to 11 amino acids in length. The groove has a closed floor and two walls that are formed by helical segments of the α chain, called α1 and α2. The groove also has pockets that can interact with specific amino acids (called anchor residues) at certain positions of the peptide. Different alleles of MHC Class I molecules have different preferences for peptide binding, which influences the strength and specificity of the immune response.

The immunoglobulin-like domain is a conserved part of the molecule that resembles a domain of an antibody molecule. It contains a binding site for a co-receptor molecule called CD8, which is expressed on CTLs and helps them to recognize MHC Class I molecules. The transmembrane and cytoplasmic domains ensure that the α chain is anchored to the cell membrane and properly expressed on the cell surface.

The β2M chain is also similar to an immunoglobulin domain, but it does not span the membrane. It associates non-covalently with the α chain and stabilizes its folding and peptide binding.

The assembly and transport of MHC Class I molecules involves several steps and molecular chaperones in the endoplasmic reticulum (ER). First, the α chain binds to a chaperone called calnexin, which helps it to fold correctly. Then, when β2M binds to the α chain, calnexin is released and another chaperone called calreticulin binds to the complex. The complex also associates with a protein called tapasin, which brings it close to a transporter protein called TAP (transporter associated with antigen processing). TAP transports peptides from the cytosol to the ER lumen, where they can bind to MHC Class I molecules. TAP prefers peptides that have hydrophobic or basic amino acids at their carboxyl terminus, which are also favored by MHC Class I molecules as anchor residues. After peptide binding, MHC Class I molecules dissociate from calreticulin and tapasin and exit from the ER via vesicles that fuse with the Golgi apparatus. From there, they are transported to the cell surface where they can present peptides to CTLs. Another chaperone protein called ERp57 may also be involved in MHC Class I assembly and loading by facilitating disulfide bond formation in the α chain.

MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules that are essential for the activation of CD4+ T cells, also known as helper T cells. These cells are involved in various immune functions, such as providing help to B cells for antibody production, enhancing phagocytosis by macrophages, and secreting cytokines that regulate inflammation and immunity .

Unlike MHC Class I molecules, which are expressed on almost all nucleated cells and present endogenous antigens (derived from the cytosol) to CD8+ T cells (cytotoxic T cells), MHC Class II molecules are normally found only on professional antigen-presenting cells (APCs), such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells . These cells are specialized in capturing, processing, and presenting exogenous antigens (derived from the extracellular environment) to CD4+ T cells .

In humans, the MHC Class II protein complex is encoded by the human leukocyte antigen (HLA) gene complex, which is located on chromosome 6. The HLA Class II region consists of three subregions: DP, DQ, and DR, each of which contains multiple genes that encode the alpha and beta chains of the MHC Class II molecules . The alpha and beta chains are non-covalently associated to form a heterodimer that has a peptide-binding groove and an immunoglobulin-like domain . The peptide-binding groove is open at both ends and can accommodate peptides of 13-18 amino acids in length . The immunoglobulin-like domain interacts with the CD4 molecule on the surface of CD4+ T cells .

The expression of MHC Class II molecules is tightly regulated by various factors, such as cytokines, transcription factors, and chaperone proteins. One of the key regulators is the MHC Class II transactivator (CIITA), which is a transcription factor that binds to the promoter regions of the MHC Class II genes and activates their expression . CIITA is constitutively expressed in professional APCs, but can also be induced in other cell types by interferon gamma (IFN-gamma), a cytokine that is secreted by activated T cells and natural killer (NK) cells .

The expression of MHC Class II molecules is crucial for the initiation and regulation of adaptive immune responses against various pathogens, such as bacteria, viruses, fungi, and parasites. It is also important for maintaining self-tolerance and preventing autoimmune diseases. However, mutations or polymorphisms in the HLA Class II genes or the CIITA gene can lead to defects in antigen presentation or recognition, resulting in impaired immunity or increased susceptibility to infections or autoimmune disorders . For example, bare lymphocyte syndrome (BLS) is a rare genetic disorder that is characterized by the absence or reduced expression of MHC Class II molecules on APCs due to mutations in the CIITA gene or other genes involved in MHC Class II expression. This causes severe combined immunodeficiency (SCID), which manifests as recurrent infections, failure to thrive, and early death .

MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells. These cells are important in initiating immune responses. The main function of MHC Class II molecules is to present processed antigens, which are derived primarily from exogenous sources, to CD4(+) T-lymphocytes. MHC Class II molecules thereby are critical for the initiation of the antigen-specific immune response.

MHC Class II molecules are dimers consisting of a 33 kDa α-chain and a 28 kDa β-chain, which are associated by non-covalent interactions . Both the α-chain and β-chain are made up of two domains: α1 and α2, and β1 and β2, respectively. They are membrane-bound glycoproteins that contain external domains, a transmembrane segment, and a cytoplasmic tail. An open-ended groove formed between the α1 and β1 domains serves as the peptide-binding cleft, which can bind antigenic peptides of 13-18 amino acid residues long.

MHC Class II molecules present antigens of exogenous origin to CD4+ T cells. Antigen-presenting cells can internalize antigens by phagocytosis, endocytosis, or both. The internalized antigens are degraded into peptides in the compartments of the endocytic processing pathway. The peptides then associate with MHC Class II molecules within the cell cytoplasm, forming a peptide-MHC complex. This complex is then transported to the cell surface, where it is displayed for recognition by appropriate T cells.

The expression of MHC Class II molecules is regulated by several factors, including cytokines, transcription factors, and accessory proteins. One of the key regulators is the MHC Class II transactivator (CIITA), which is a transcription factor that activates the expression of MHC Class II genes as well as other genes involved in antigen presentation. CIITA is expressed mainly on professional antigen-presenting cells but can also be induced on other cells by interferon-γ (IFN-γ). Another important factor is the invariant chain (Ii), which is a protein that associates with newly synthesized MHC Class II molecules in the endoplasmic reticulum and prevents them from binding endogenous peptides. Ii also facilitates the transport of MHC Class II molecules to the endocytic pathway, where it is gradually cleaved by proteases, leaving a short fragment called CLIP (Class II-associated invariant chain peptide) that occupies the peptide-binding groove until it is replaced by an exogenous peptide with the help of HLA-DM, a non-classical MHC molecule that catalyzes peptide exchange .

MHC Class II molecules play a vital role in adaptive immunity by activating helper T cells that can provide signals for B cell activation and antibody production, cytotoxic T cell differentiation and proliferation, macrophage activation and inflammation, and regulatory T cell induction and suppression. MHC Class II molecules also participate in thymic selection and education of T cells by presenting self-peptides to developing T cells and deleting or tolerizing those that react strongly with self-antigens. However, aberrant expression or function of MHC Class II molecules can also contribute to autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes mellitus, multiple sclerosis, and Graves` disease. Therefore, understanding the structure and function of MHC Class II molecules is essential for developing novel strategies for immunotherapy and vaccination.

MHC Class III is a group of genes that are located between MHC Class I and MHC Class II genes on chromosome 6 in humans. Unlike MHC Class I and II, which encode for cell surface proteins that present antigenic peptides to T cells, MHC Class III genes encode for various secreted proteins that have immune functions, such as cytokines and complement proteins.

Cytokines are soluble molecules that regulate inflammation, immunity, and hematopoiesis. Some of the cytokines encoded by MHC Class III genes are tumor necrosis factor (TNF), lymphotoxin (LT), and interleukin-10 (IL-10). TNF and LT are pro-inflammatory cytokines that mediate cell death, inflammation, and tissue damage in response to infection or injury. IL-10 is an anti-inflammatory cytokine that inhibits the production of other cytokines and modulates the immune response.

Complement proteins are a group of plasma proteins that participate in the innate immune system. They can be activated by different pathways and mediate various functions, such as opsonization, phagocytosis, inflammation, and lysis of pathogens. Some of the complement proteins encoded by MHC Class III genes are C2, C4a, C4b, and factor B. C2 and C4 are components of the classical and lectin pathways of complement activation. C4a and C4b are cleavage products of C4 that have different roles. C4a is an anaphylatoxin that induces inflammation and vasodilation. C4b is a covalently bound opsonin that enhances phagocytosis. Factor B is a component of the alternative pathway of complement activation. It forms a complex with C3b and acts as a substrate for factor D, which cleaves it into Ba and Bb. Bb is a serine protease that activates C3 and C5.

MHC Class III genes are important for the immune response because they regulate the activation, differentiation, and effector functions of various immune cells. They also contribute to the clearance of pathogens and the resolution of inflammation. However, some MHC Class III genes are also associated with autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D). This is because some variants of these genes may alter the expression or function of cytokines or complement proteins, leading to dysregulation of the immune system and tissue damage.

Antigen processing and presentation is the mechanism by which whole antigens are degraded and loaded onto MHC molecules for display on the cell surface for recognition by T cells. Both macrophages and dendritic cells (DCs) are considered professional antigen-presenting cells, although DCs possess the unique capacity to activate naive T cells. Antigen processing and presentation can be divided into six discrete steps:

1. Acquisition of antigens: Antigens can be derived from endogenous sources (such as viral proteins or tumor antigens) or exogenous sources (such as bacteria or parasites). Endogenous antigens are processed by the cytosolic pathway and presented by MHC class I molecules, while exogenous antigens are processed by the endocytic pathway and presented by MHC class II molecules .
2. Tagging of antigens for degradation: Antigens destined for presentation need to be marked for degradation by various mechanisms, such as ubiquitination, glycosylation or acetylation. These tags target the antigens to specific proteases that cleave them into peptides .
3. Degradation of antigens into peptides: Antigens are degraded into peptides by different proteases depending on the source and the pathway of processing. For endogenous antigens, the main protease is the proteasome, a large multicatalytic complex that degrades ubiquitinated proteins in an ATP-dependent manner. For exogenous antigens, the main proteases are lysosomal enzymes, such as cathepsins, that degrade internalized antigens in acidic compartments .
4. Transport of peptides to MHC-loading compartments: Peptides generated by antigen processing need to be transported to specific compartments where they can associate with MHC molecules. For endogenous peptides, this compartment is the endoplasmic reticulum (ER), where MHC class I molecules are synthesized and assembled. For exogenous peptides, this compartment is the endocytic vesicle, where MHC class II molecules are delivered from the trans-Golgi network .
5. Loading of peptides onto MHC molecules: Peptides bind to the peptide-binding groove of MHC molecules in a specific and stable manner. The binding affinity and specificity depend on the length, sequence and conformation of the peptide, as well as the polymorphic residues of the MHC molecule. Peptide loading is facilitated by various accessory molecules, such as chaperones, tapasin and HLA-DM .
6. Expression of peptide-MHC complexes on the cell surface: Peptide-MHC complexes are transported from the loading compartments to the cell surface via vesicular trafficking. The expression level and stability of peptide-MHC complexes depend on several factors, such as peptide availability, MHC polymorphism, antigen processing efficiency and T cell feedback .

Antigen processing and presentation is essential for adaptive immunity, as it allows T cells to recognize foreign or altered self-antigens and mount specific responses against them. However, antigen processing and presentation also poses challenges for immune regulation, such as avoiding self-reactivity, tolerating commensal microbes and escaping immune evasion by pathogens . Therefore, antigen processing and presentation is a dynamic and complex process that is tightly regulated at multiple levels.

The cytosolic pathway is used to process and present antigens that are derived from the cell`s own proteins or from intracellular pathogens, such as viruses or bacteria that reside in the cytoplasm. These antigens are presented by MHC class I molecules to CD8+ T cells, which can then kill the infected or abnormal cells.

The main steps of the cytosolic pathway are:

• Proteolytic degradation of antigens into peptides: The proteins that need to be degraded are marked with a small protein called ubiquitin, which targets them for destruction by a large protease complex called the proteasome. The proteasome cleaves the proteins into short peptides of about 8-10 amino acids, which are optimal for binding to MHC class I molecules. The proteasome also prefers to cut at certain amino acids, generating peptides with hydrophobic or basic residues at the carboxyl terminus, which are also favored by MHC class I molecules .
• Transport of peptides from cytosol to endoplasmic reticulum: The peptides that are generated in the cytosol by the proteasome are transported across the membrane of the endoplasmic reticulum (ER) by a protein complex called TAP (transporter associated with antigen processing). TAP is composed of two subunits, TAP1 and TAP2, which belong to the family of ATP-binding cassette (ABC) transporters. TAP uses ATP hydrolysis to pump the peptides into the ER lumen, where they encounter MHC class I molecules .
• Assembly of peptides with MHC class I molecules: The MHC class I molecules are synthesized in the ER and consist of two chains: a heavy chain (or alpha chain) that spans the membrane and a light chain (or beta-2 microglobulin) that is non-covalently associated with it. The heavy chain has three domains: alpha-1 and alpha-2 form the peptide-binding groove, and alpha-3 is similar to an immunoglobulin domain. The heavy chain also has a transmembrane domain and a cytoplasmic tail. The MHC class I molecules need to bind a peptide in order to fold properly and exit the ER. To prevent premature binding of peptides in the ER, the MHC class I molecules associate with several chaperone proteins, such as calnexin, calreticulin, ERp57, and tapasin. Tapasin is especially important for bringing the MHC class I molecules close to the TAP transporter and facilitating peptide loading. Once a peptide binds to the MHC class I molecule, it stabilizes its conformation and allows it to dissociate from the chaperones and proceed to the cell surface via the Golgi apparatus .

The endocytic pathway processes and presents exogenous antigens, that is, antigens that are derived from outside the cell, such as bacteria, viruses, or soluble proteins. These antigens are internalized by antigen-presenting cells (APCs) through phagocytosis, endocytosis, or receptor-mediated uptake. The internalized antigens are then delivered to acidic compartments called endosomes, where they encounter various proteolytic enzymes that degrade them into peptides. The endosomes can be classified into early endosomes (pH 6.0-6.5), late endosomes or endolysosomes (pH 5.0-6.0), and lysosomes (pH 4.5-5.0), with increasing proteolytic activity from one compartment to the next .

The peptides generated in the endocytic pathway are then loaded onto MHC class II molecules, which are specialized for presenting exogenous antigens to CD4+ T cells. The MHC class II molecules are synthesized in the rough endoplasmic reticulum (RER) and associate with a protein called invariant chain (Ii), which prevents them from binding endogenous peptides in the RER . The MHC class II-Ii complexes are then transported to the trans-Golgi network and sorted into vesicles that fuse with the endocytic compartments . In the endosomes, the invariant chain is gradually cleaved by proteases, leaving a short fragment called CLIP (class II-associated invariant chain peptide) that occupies the peptide-binding groove of the MHC class II molecule . CLIP is then exchanged for an antigenic peptide with the help of a molecule called HLA-DM, which catalyzes the release of CLIP and the binding of a suitable peptide . HLA-DM is another non-classical MHC class II molecule that is expressed in the endocytic compartments and regulates peptide loading . HLA-DM can also be modulated by another molecule called HLA-DO, which binds to HLA-DM and reduces its efficiency of CLIP exchange . HLA-DO is mainly expressed in B cells and may play a role in shaping the antigen repertoire for MHC class II presentation .

After loading an antigenic peptide, the MHC class II-peptide complex dissociates from HLA-DM and other chaperone proteins and travels to the cell surface via vesicular transport . There, it can be recognized by CD4+ T cells that express a T cell receptor (TCR) specific for the peptide-MHC class II combination. This recognition leads to T cell activation and differentiation into various effector and memory subsets that mediate immune responses against exogenous antigens.

TAP stands for transporter associated with antigen processing. It is a protein complex that belongs to the ATP-binding-cassette (ABC) transporter family. It delivers cytosolic peptides into the endoplasmic reticulum (ER), where they bind to nascent MHC class I molecules.

TAP is composed of two subunits: TAP1 and TAP2, which have one hydrophobic region and one ATP-binding region each. They form a heterodimer, which results in a four-domain transporter.

TAP-mediated peptide transport is a multistep process. The peptide-binding pocket is formed by TAP1 and TAP2. Peptides are recognized and bound by TAP in an ATP-independent manner, followed by a slow conformational change of the TAP complex. This triggers ATP hydrolysis and initiates peptide translocation across the ER membrane.

Both nucleotide-binding domains (NBDs) are required for peptide translocation, as each NBD cannot hydrolyze ATP alone. The exact mechanism of transport is not fully understood, but it is suggested that ATP binding to TAP1 is the initial step, and that ATP bound to TAP1 induces ATP binding in TAP2.

TAP is essential for the assembly and presentation of MHC class I molecules. TAP associates with the peptide-loading complex (PLC), which consists of β2 microglobulin, calreticulin, ERp57, tapasin, and MHC class I. The PLC stabilizes and facilitates the loading of peptides onto MHC class I molecules.

TAP has a high affinity for peptides of 8-10 amino acids in length, which are optimal for MHC class I binding. TAP also prefers peptides with hydrophobic or basic carboxyl-terminal amino acids, which are preferred anchor residues for MHC class I molecules. Thus, TAP is optimized to transport peptides that will interact with MHC class I molecules.

TAP plays a crucial role in the processing and presentation of MHC class I restricted antigens, which are essential for the activation of CD8+ cytotoxic T cells. T cells recognize peptides derived from endogenous antigens, such as viral proteins or tumor proteins, that are processed by the cytosolic pathway and transported by TAP into the ER.

TAP deficiency leads to impaired MHC class I expression and presentation, resulting in increased susceptibility to viral infections and tumors. TAP deficiency is also associated with autoimmune diseases, such as ankylosing spondylitis and type 1 diabetes mellitus.

The invariant chain (Ii, CD74) is a protein that plays a crucial role in the antigen presentation pathway of MHC class II molecules. It is involved in the following aspects:

• Formation and transport of MHC class II complexes. The invariant chain associates with three pairs of MHC class II alpha and beta chains in the endoplasmic reticulum (ER), forming a nonameric complex. The invariant chain binds to the peptide-binding groove of the MHC class II molecules, preventing them from binding to endogenous peptides in the ER. The invariant chain also facilitates the folding and assembly of the MHC class II molecules and directs their exit from the ER to the Golgi apparatus. From there, the MHC class II-invariant chain complexes are sorted to the endocytic pathway, where they encounter exogenous antigens that have been internalized and degraded by antigen-presenting cells (APCs).
• Regulation of antigen processing and loading. The invariant chain undergoes gradual proteolytic cleavage by various enzymes in the endocytic compartments, leaving a short fragment called CLIP (class II-associated invariant chain peptide) that remains bound to the MHC class II molecules. CLIP prevents premature binding of antigenic peptides to the MHC class II molecules until they reach the late endosomes or lysosomes, where they encounter HLA-DM. HLA-DM is a non-classical MHC class II molecule that catalyzes the exchange of CLIP for antigenic peptides, allowing the formation of stable peptide-MHC class II complexes. HLA-DM also edits the peptide repertoire by favoring peptides with high affinity and stability for MHC class II molecules. HLA-DO is another non-classical MHC class II molecule that modulates the activity of HLA-DM by inhibiting its ability to remove CLIP and edit peptides. HLA-DO expression is regulated by cytokines and cellular activation status.
• Influence on endosomal trafficking, cell migration and signal transduction. The invariant chain has several functions beyond antigen presentation that are mediated by its cytoplasmic tail or its extracellular domain. The cytoplasmic tail contains motifs that interact with various proteins involved in vesicular transport, such as AP-1, AP-2, AP-3, clathrin and rab5. These interactions affect the sorting and trafficking of MHC class II-invariant chain complexes and other molecules within the endocytic pathway. The extracellular domain of the invariant chain can act as a receptor for macrophage migration inhibitory factor (MIF), a cytokine that regulates inflammation and immunity. The binding of MIF to the invariant chain triggers intracellular signaling pathways that modulate cell survival, proliferation, migration and cytokine production.

In summary, the invariant chain is a multifaceted protein that plays an essential role in antigen presentation by MHC class II molecules. It also influences other cellular processes that are relevant for immune responses.

Besides peptides, T cells can also recognize non-peptide antigens, such as lipids, glycolipids, and phosphoantigens. These antigens are presented by non-classical MHC molecules, such as CD1 and MR1, or by TCRγδ. Non-peptide antigens are derived from various sources, such as bacteria, fungi, parasites, and tumors, and can elicit potent immune responses against these pathogens or malignancies.

CD1 molecules are a family of glycoproteins that share structural similarity with MHC class I molecules, but have a more hydrophobic and spacious antigen-binding groove that can accommodate lipid-based antigens. CD1 molecules are classified into two groups: group 1 (CD1a, CD1b, CD1c, and CD1e) and group 2 (CD1d). Group 1 CD1 molecules present various microbial lipids and lipoglycans, such as mycolic acids and lipoarabinomannan from Mycobacterium tuberculosis, to T cells expressing αβ TCRs. Group 2 CD1 molecule (CD1d) presents glycosphingolipids, such as α-galactosylceramide from marine sponges, to a subset of T cells called natural killer T (NKT) cells, which express semi-invariant αβ TCRs.

MR1 (MHC class I-related protein 1) is another non-classical MHC molecule that can present non-peptide antigens to T cells. MR1 presents vitamin B metabolites, such as 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), derived from bacteria and some fungi. These antigens are recognized by a subset of T cells called mucosal-associated invariant T (MAIT) cells, which express semi-invariant αβ TCRs.

Phosphoantigens are small phosphorylated molecules that are produced by the non-mevalonate pathway of isoprenoid biosynthesis in many bacteria and parasites. The most potent phosphoantigen is (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), which is absent from human cells. Phosphoantigens are recognized by a subset of T cells expressing γδ TCRs, especially those bearing Vγ9Vδ2 chains. These T cells can also be activated by synthetic aminobisphosphonates, such as zoledronate, which are used to treat osteoporosis and bone metastases.

Non-peptide antigens play important roles in the immune system by activating various subsets of T cells that have distinct functions and phenotypes. These T cells can produce cytokines, kill infected or transformed cells, regulate other immune cells, and mediate tissue repair and homeostasis. Therefore, non-peptide antigens are potential targets for immunotherapy and vaccine development against infectious diseases and cancers.

Antigen processing and presentation are essential for the activation of T cells and the generation of adaptive immune responses. However, abnormalities or defects in these pathways can have various clinical implications, such as:

• Increased susceptibility to infections: Some pathogens can interfere with antigen processing and presentation by inhibiting the expression or function of MHC molecules, TAP proteins, proteasomes or invariant chains. For example, human cytomegalovirus (HCMV) encodes proteins that block the transport of MHC class I molecules to the cell surface, preventing the recognition of infected cells by CD8+ T cells. Similarly, Mycobacterium tuberculosis can inhibit the fusion of phagosomes with lysosomes, impairing the degradation and presentation of bacterial antigens by MHC class II molecules. These strategies allow the pathogens to evade immune detection and clearance, leading to persistent or chronic infections.

• Autoimmune diseases: Some autoimmune diseases are associated with certain alleles of MHC molecules that present self-antigens to autoreactive T cells. For example, type 1 diabetes mellitus is linked to HLA-DQ and HLA-DR alleles that present peptides derived from pancreatic beta-cell antigens, such as insulin or glutamic acid decarboxylase. Similarly, rheumatoid arthritis is associated with HLA-DR alleles that present peptides derived from citrullinated proteins, which are modified by a post-translational process that occurs in inflamed tissues. The presentation of these self-antigens triggers an inflammatory response that damages the target organs.

• Cancer: Antigen processing and presentation are crucial for the elimination of malignant cells by cytotoxic CD8+ T cells. However, some cancer cells can escape immune surveillance by downregulating or losing the expression of MHC class I molecules, TAP proteins or proteasomes. This reduces the presentation of tumor-associated antigens and prevents the recognition and killing of cancer cells by CD8+ T cells. Moreover, some cancer cells can express immunosuppressive molecules, such as PD-L1, that bind to PD-1 receptors on T cells and inhibit their activation. These mechanisms contribute to tumor progression and resistance to immunotherapy.

Therefore, antigen processing and presentation are important for maintaining immune homeostasis and protecting against various diseases. Understanding how these pathways are regulated and modulated can help to develop novel strategies for enhancing or restoring immune responses against infections and cancer, or for preventing or treating autoimmune diseases.

We are Compiling this Section. Thanks for your understanding.