Antigen Processing, and Presentation – MHC Class I, Class II,

Antigen processing and presentation is a biological mechanism by which the immune system detect the foreign antigen and abnormal cell. It is important for activation of T lymphocytes. It helps in formation of specific adaptive immune response against pathogen.

In this process, the foreign antigen such as viral protein, bacterial protein or abnormal cellular protein is first broken down into small peptide fragments. This step is called antigen processing. The breakdown is done by different cellular enzymes present inside the cell.

After processing, the small peptide fragments bind with Major Histocompatibility Complex (MHC) molecules. MHC molecules act as transport and display proteins. They carry the processed peptide from inside of the cell to the cell surface.

The peptide bound with MHC forms a peptide-MHC complex. This complex is then transported to the surface of antigen presenting cell. This outward display of antigen is called antigen presentation.

During this process, T cells examine the presented peptide. If the peptide is recognized as foreign or abnormal, then T lymphocytes become activated. After activation, they start immune response which helps to remove infection, pathogen or abnormal cells.

Antigen processing and presentation is a link between antigen detection and activation of adaptive immunity. It makes the antigen visible to the immune cells. This is needed for proper and specific immune defence.

Major Histocompatibility Complex Class I (MHC Class I)

Major Histocompatibility Complex Class I (MHC Class I) is a membrane glycoprotein molecule which present antigen peptide on the surface of cell. It acts like a transport and display molecule for the immune system. It helps T cells to check what is present inside the cell.

MHC Class I is present on almost all nucleated cells of body. It is not present on mature red blood cells because they have no nucleus. It mainly present the endogenous antigen, which are formed inside the cell.

The structure of MHC Class I is made up of one heavy α-chain and one small light chain called β₂-microglobulin. The peptide binding groove is present in the α-chain. This groove has closed ends, so it binds short peptide fragments.

The peptide carried by MHC Class I is generally 8 to 10 amino acids long. These peptides may come from normal self protein, viral protein or abnormal tumour protein. After binding, the peptide-MHC complex comes to the cell surface.

MHC Class I present antigen mainly to CD8⁺ cytotoxic T cells. If the CD8⁺ T cell recognize the peptide as foreign or abnormal, then it become activated. Then it kills the infected cell or tumour cell.

In cancer cells, MHC Class I expression may be reduced or lost. This helps the tumour cell to escape from T cell recognition. So MHC Class I is very important for detection of virus infected cells and malignant cells.

Structure of Major Histocompatibility Complex Class I (MHC Class I)

• MHC Class I is a heterodimer molecule. It is formed by one heavy α-chain and one small β₂-microglobulin chain.
• Heavy α-chain is about 45 kDa. It is polymorphic chain. It is the main chain of MHC Class I.
• β₂-microglobulin is about 12 kDa. It is monomorphic chain. It is light chain and it is not membrane inserted.
• Heavy α-chain is fixed in the cell membrane. β₂-microglobulin remain attached with it from outside.
• The heavy α-chain has three outer domains. These are α₁ domain, α₂ domain and α₃ domain.
• After these domains, a connecting peptide is present. Then transmembrane part is present. Then a small cytoplasmic tail is present.
• α₁ and α₂ domains form the peptide binding groove. This is the antigen holding part of MHC Class I.
• The floor of groove is made by β-pleated sheet. It has eight strands. Two α-helices are present at the sides.
• The groove is closed at both ends. Conserved tyrosine residues make this closed condition.
• Due to closed ends, long peptide cannot bind. Only short peptide bind in it. Usually 8 to 10 amino acid peptide is present.
• The groove has deep pockets for holding peptide. A pocket and F pocket are important pocket.
• A pocket bind the amino end of peptide. F pocket bind the carboxyl end of peptide.
• The two ends of peptide are held by hydrogen bonds. So peptide become fixed in the groove.
• The middle portion of peptide may come upward from groove. This exposed part is available for T-cell receptor (TCR).
• α₃ domain is present near the membrane. It is an immunoglobulin like domain.
• α₃ domain does not hold peptide. It is used for binding with CD8α molecule.
• CD8α is present on cytotoxic T cell. So α₃ domain help in contact between MHC Class I and CD8⁺ T cell.
• β₂-microglobulin bind with heavy α-chain by non-covalent bond. It gives stability to the molecule.
• β₂-microglobulin also support the peptide binding floor. A hydrophobic part fit into the β-sheet region.
• Heavy α-chain gene is present on chromosome 6. β₂-microglobulin gene is present on chromosome 15.
• So, MHC Class I has heavy α-chain, β₂-microglobulin, peptide binding groove, transmembrane region and cytoplasmic tail. It presents endogenous peptide to CD8⁺ cytotoxic T cell.

Major histocompatibility complex II (MHC Class II)

Major histocompatibility complex II (MHC Class II) is a membrane glycoprotein molecule which present processed antigen on the surface of cell. It is mainly used for presentation of exogenous antigen. It helps CD4⁺ helper T cells to recognize the foreign antigen.

MHC Class II is present mainly on professional antigen presenting cells (APCs). These are dendritic cells, macrophages and B lymphocytes. It is not present on all nucleated cells like MHC Class I.

The antigen of MHC Class II comes from outside of the cell. It may be bacterial antigen, fungal antigen, parasite antigen or toxin. These antigen are taken inside the cell and then degraded in endosomal vesicle.

MHC Class II molecule is made up of two membrane bound chains. One is α-chain and another is β-chain. Both chains are almost similar in size and both form the peptide binding groove.

The peptide binding groove of MHC Class II is open at both ends. So longer peptide can bind in it. The peptide is generally 12 to 25 amino acid long.

After binding of peptide, the peptide-MHC Class II complex comes on the cell surface. Then CD4⁺ helper T cell recognize it. If the antigen is foreign, the helper T cell becomes activated.

Activated CD4⁺ T cell produce cytokines. It help B cell for antibody production. It also activate macrophages for killing of pathogen.

In human, MHC Class II genes are called HLA genes. The main types are HLA-DR, HLA-DP and HLA-DQ.

Structure of Major Histocompatibility Complex Class II (MHC Class II)

• MHC Class II is a heterodimeric protein. It is made up of two different chains. One is α-chain and another is β-chain.
• The α-chain is about 33 kDa. The β-chain is about 29 kDa. Both chains are almost same size and both are transmembrane chain.
• Both α-chain and β-chain are inserted in cell membrane. So MHC Class II is a membrane bound molecule.
• The α-chain has two outer domains. These are α₁ domain and α₂ domain.
• The β-chain also has two outer domains. These are β₁ domain and β₂ domain.
• α₁ and β₁ domains are present at the outer side. These two domains together form the peptide binding groove.
• The peptide binding groove is the antigen holding part of MHC Class II. Here the processed antigen peptide is placed.
• The groove of MHC Class II is open at both ends. So the peptide can extend out from the two side of the groove.
• Due to open ends, longer peptide can bind in it. The peptide is generally 12 to 25 amino acid long.
• The bound peptide lie in extended form. Some extra peptide part remain outside the groove. These are called peptide flanking residues (PFRs).
• MHC Class II groove does not mainly hold the absolute terminal ends of peptide. It mainly bind a core 9 amino acid region.
• This core region is fixed by hydrogen bonds along the peptide backbone. So the peptide become stable in the groove.
• The groove has some important binding pockets. These are P1, P4, P6, P7 and P9 pockets.
• These pockets bind with side chain of peptide. The pockets are polymorphic. So different MHC Class II molecule can bind different peptide.
• P1 pocket is deep and hydrophobic pocket. It gives main binding stability to the peptide.
• α₂ and β₂ domains are present near the membrane. These domains give support to upper peptide binding region.
• α₂ and β₂ domains also take part in binding with CD4 co-receptor. CD4 is present on helper T cell.
• The CD4 binding site is a non-polymorphic hydrophobic concavity. It is formed by membrane proximal α₂ and β₂ domains.
• This CD4-MHC Class II interaction is important for activation of CD4⁺ helper T cell.
• During formation in endoplasmic reticulum (ER), the groove of MHC Class II is blocked by invariant chain (Ii).
• Invariant chain (Ii) act as assembly chaperone. It prevent early binding of unwanted intracellular peptide.
• After this, MHC Class II goes to endosomal compartment. There the actual exogenous antigen peptide is loaded.
• Thus MHC Class II structure has two membrane bound chains, four outer domains, open peptide binding groove, binding pockets and CD4 binding region. It is made for presentation of exogenous peptide to CD4⁺ helper T cell.

Major Histocompatibility Complex Class III (MHC Class III)

Major Histocompatibility Complex Class III (MHC Class III) is a group of genes present in the MHC region. It does not present antigen to T cells like MHC Class I and MHC Class II. It code for different immune proteins.

MHC Class III is present between the MHC Class I and MHC Class II gene regions. These genes are important for immune reaction. But they are not antigen binding molecule.

The main products of MHC Class III genes are complement proteins. These include C2, C4 and factor B. These proteins help in complement pathway and destruction of pathogen.

Some cytokines are also coded from this region. Important cytokines are TNF-α and lymphotoxin (TNF-β). These are involved in inflammation and immune cell activation.

Some genes of MHC Class III are highly polymorphic. Mainly C4 genes show variation. But the exact adaptive importance of this variation is not fully clear.

So MHC Class III is not a peptide presenting class. It is a gene region for complement proteins, cytokines and some other immune related molecules.

Structure of Major Histocompatibility Complex Class III (MHC Class III)

• MHC Class III has no fixed molecular structure. It is not like MHC Class I or MHC Class II molecule.
• It does not form one antigen presenting molecule. It has no peptide binding groove.
• It has no α-chain and β-chain arrangement for holding antigen peptide.
• It is not a membrane bound antigen transport system. It does not carry peptide to T cell.
• MHC Class III is mainly a gene region. It is present in the major histocompatibility complex (MHC) region.
• This region is located between MHC Class I and MHC Class II gene region.
• The genes of MHC Class III code many different immune proteins. These proteins are not similar in structure.
• The important products are complement proteins. These are C2, C4 and Factor B.
• C2, C4 and Factor B take part in complement cascade. They help in immune defence and pathogen destruction.
• The region also code some cytokine proteins. Important cytokines are TNF-α and lymphotoxin (TNF-β).
• TNF-α and TNF-β are immune signalling proteins. They are involved in inflammation and immune cell activity.
• So, MHC Class III is structurally not one molecule. It is a group of genes producing different immune proteins.
• Thus MHC Class III is different from MHC Class I and MHC Class II. It is not for antigen presentation, but it is important in complement reaction and inflammatory response.

Mechanism of Antigen Processing and Presentation

A. MHC Class I pathway

1. In MHC Class I pathway, the antigen is produced inside the cell. These are called endogenous antigen. It may be viral protein, tumour protein or abnormal protein formed in cytoplasm.
2. The intracellular protein is broken into short peptide fragment by proteasome. Proteasome is a cylindrical enzyme complex. It cut the protein into small antigenic peptide.
3. The peptide fragments are then transported from cytoplasm into endoplasmic reticulum (ER) by TAP. TAP means Transporter Associated with Antigen Processing. It pump the peptide into ER lumen.
4. In ER, the peptide is trimmed by ERAAP. This enzyme make the peptide proper size. The peptide become mostly 8 to 10 amino acid long.
5. In the same ER, MHC Class I heavy α-chain and β₂-microglobulin are formed. These chains join with help of chaperone proteins like calnexin, calreticulin, ERp57 and tapasin.
6. The peptide is loaded into the closed groove of MHC Class I. Tapasin help in this loading. The peptide must fit strongly in the groove.
7. After proper peptide binding, peptide-MHC Class I complex become stable. Then it leave the chaperone proteins and passes through Golgi apparatus.
8. The complex comes to the cell surface. Here CD8⁺ cytotoxic T cell recognize the peptide. If peptide is foreign or abnormal, the CD8⁺ T cell become activated and kill that infected or tumour cell.

B. MHC Class II pathway

1. In MHC Class II pathway, the antigen comes from outside of the cell. These are called exogenous antigen. It may be bacterial antigen, fungal antigen, parasite antigen or toxin.
2. The antigen is taken inside by professional antigen presenting cells (APCs). These cells are dendritic cell, macrophage and B lymphocyte. The antigen is enclosed in vesicle called endosome.
3. The endosome become acidic during movement inside the cell. In this acidic condition, cathepsins are activated. These enzymes digest the foreign protein into longer peptide fragment.
4. The peptide fragments are usually 13 to 25 amino acid long. These peptides are made ready for binding with MHC Class II molecule.
5. At the same time, MHC Class II α-chain and β-chain are synthesized in ER. The peptide binding groove is blocked by invariant chain (Ii), so self peptide cannot bind early.
6. The invariant chain-MHC Class II complex goes to special acidic vesicle called MIIC. This compartment fuse with endosome which has degraded antigen peptide.
7. Inside MIIC, the invariant chain is digested. Only small fragment remain in groove. This fragment is called CLIP.
8. HLA-DM remove CLIP from the groove. Then exogenous peptide bind into the open groove of MHC Class II molecule.
9. After peptide loading, peptide-MHC Class II complex become stable. It is transported to the cell surface.
10. On the surface, CD4⁺ helper T cell recognize the peptide. If antigen is foreign, CD4⁺ T cell become activated and produce cytokines.
11. Activated CD4⁺ helper T cell help B cell for antibody production. It also activate macrophage for killing of pathogen.

C. Cross presentation pathway

1. Cross presentation is a special antigen presentation pathway. In this pathway, exogenous antigen is presented by MHC Class I molecule.
2. This process is mainly done by special dendritic cells. The antigen may come from virus infected dead cell or tumour cell debris.
3. In vacuolar pathway, the antigen stay inside vesicle. It is degraded by lysosomal proteases and peptide is loaded on MHC Class I inside vesicle.
4. In cytosolic pathway, the antigen comes out from endosome into cytoplasm. Then it is degraded by proteasome and peptide is transported by TAP into ER or endosome.
5. After loading of peptide, peptide-MHC Class I complex comes to the dendritic cell surface. It is shown to CD8⁺ cytotoxic T cell.
6. This process help to activate CD8⁺ T cells against virus infected cells and tumour cells. It is important when the APC itself is not directly infected.

Clinical Significance of Antigen Processing and Presentation

• Vaccine development
  Antigen processing and presentation is important in vaccine action. Vaccine antigen is taken up by antigen presenting cells and then processed and presented on MHC molecules. This helps in activation of T cells and formation of long lasting immune memory.
• Cancer immunotherapy
  In cancer vaccine, proper antigen presentation is required for killing of tumour cells. Dendritic cells can present tumour antigen by cross presentation pathway. This activate CD8⁺ cytotoxic T cells which destroy tumour cell.
• Cancer immune escape
  Many tumour cells reduce or lose MHC Class I expression. Due to this, tumour antigen is not properly shown to CD8⁺ T cells. So the tumour cell become less visible to immune system.
• Natural killer cell response
  When tumour cell lose MHC Class I, it may escape from T cells. But this same condition can make it target for Natural Killer (NK) cells. Because NK cells can detect cells with low MHC Class I.
• Immune suppression by tumour
  Some tumour cells increase non-classical HLA-G molecule. HLA-G suppress the immune response. Its high expression is related with metastasis and poor prognosis in many cancer.
• Autoimmune diseases
  Improper antigen processing and presentation may cause autoimmune disease. In this condition self antigen is presented wrongly or tolerance is not properly formed. It is related with Type 1 diabetes, Rheumatoid arthritis and Multiple sclerosis.
• AIRE gene defect
  Mutation in AIRE gene causes improper presentation of self antigen in thymus. Then self reactive immune cells are not removed properly. This may cause autoimmune attack on endocrine organs, called APECED or APS1.
• Transplant rejection
  MHC or HLA molecules are highly polymorphic. So they differ from one person to another person. If donor and recipient HLA are not matched, recipient T cells recognize the graft as foreign and reject it.
• Graft acceptance
  Some non-classical HLA molecules help in graft tolerance. HLA-G is one important molecule. It can reduce immune attack and help in acceptance of transplanted tissue.
• Viral immune evasion
  Many viruses block antigen presentation. Adenovirus can stop MHC Class I molecule from leaving endoplasmic reticulum (ER). So viral peptide is not shown properly to CD8⁺ T cells.
• Pathogen escape from MHC binding
  Some viruses change their antigenic protein. Epstein-Barr virus can make such changes so peptide cannot bind properly with some host MHC alleles. This helps the virus to escape from immune recognition.
• Cross presentation as backup pathway
  Cross presentation is important when virus infected cell cannot present antigen properly. Uninfected dendritic cells take antigen from infected dead cell and present it by MHC Class I. This activate CD8⁺ T cells.
• Diagnostic marker
  Some antigen presentation molecules are used as clinical marker. Soluble HLA-G in blood is studied as liquid biopsy marker. It may help in cancer screening, prognosis and chronic infection monitoring.
• Advanced T cell diagnosis
  Changes in peptide flanking residues (PFRs) of MHC Class II bound peptide can affect CD4⁺ T cell recognition. This is useful for developing better CD4⁺ T cell based diagnostic methods.

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