Whenever a foreign organism invades our body, the immune system receives an alert. This is due to the presence of small glycoprotein antigens on the surface of these invading organisms that the body identifies as foreign.
All cells carry antigens on their surface; the body can distinguish the different self- and non-self-antigens because of the selection process during birth and in early years of life. Initially, due to the great diversity of DNA splicing and recombination, the immune system creates billions of different antibodies with a limited number of genes by rearranging DNA segments during B cell development, prior to antigen exposure.
This results in formation of lymphocytes complimentary to every possible antigen, even those of the fetus itself. Our lymphocytes are then matured, and T-cells are carried to the thymus, while B-cells are sent to the bone marrow for further processing.
In these locations, respective lymphocytes are exposed to every antigen in the fetus’ body. Whichever lymphocyte reacts, it is killed on the spot. So, normally, a human being does not have those lymphocytes that correspond to the self-antigens.
Now, only those lymphocytes are present that will essentially attack foreign antigens. However, these are stored in numerous peripheral and central lymph node organs, in inactive state. An antigen needs to be transported to them for activation.
To perceive and battle the extensive variety of pathogens that an individual will experience in their lifetime, lymphocytes of the adaptive immune system have developed ways to identify an incredible assortment of various antigens from micro-organisms, infections and other.
Recognition of Antigens
The antigen-identifying parts of B-cells are the immunoglobulins (Ig). These proteins are created by B-cells in an array of antigen specificities, with every B-cell delivering an immunoglobulin of a single specificity. Some of these are bound to the B-cell surface and serve as the cell’s antigen receptor. They are known as the B-cell receptor (BCR).
Immunoglobulins of similar antigen specificity are released into the extracellular fluid (ECF) as an immune response by mature B-cells, the plasma cells. The discharge of antibodies, which bind pathogens in extracellular spaces of the body, is the fundamental effector capacity of B-cells.
T-cells, on the other hand, have antigen-recognizing proteins on their cell membrane; they are called TCRs (T-cell receptors) and bear an enormous similarity to the antibodies of B-cells. They even have both the V and C regions and are produced by a process of variability not very different from that of B-cells, as mentioned above.
However, there is one difference: T-cells do not recognize antigens like B-cells do. On the contrary, T-cells need their antigens to be presented as short peptides, bound to special Major Histocompatibility Complex (MHC) molecules. Only then will the antigens be effective and will be able to activate the T-cells.
These antigens are presented to the T-cells via specific molecules, which are present on the antigen presenting cells. The protein antigens are presented by the MHC molecules, which are coded by a specific segment of DNA. On the other hand, the lipid antigens are presented by the CD1 molecules. These are explained in more detail below.
It’s important to note that T-cells only respond to processed antigens, which are short amino acid sequences called peptides. Therefore, only those antigens that have been broken down into peptides will be effective in eliciting a response. This is called antigen processing.
It all begins with the invasion of foreign organisms. These are ingested by the antigen presenting cells. Antigen presenting cells are of 3 types, but the majority of them include dendritic cells.
Once foreign organisms are phagocytosed, they form an endosome, which is fused with lysosomes that contain enzymes to kill and digest the organisms.
Antigens are, however, conserved. They are taken to the endoplasmic reticulum where they are processed to form small peptides. These peptides are then combined with MHC molecules and expressed on the cell surfaces. Thus, they are once again capable of activating T-cells by attaching to relevant T-cell molecules with complimentary TCRs.
Types of MHC Molecules
The function of MHC molecules is to bind and express antigen peptides—derived from pathogens—on the cell surface, so that they are acknowledged by the appropriate T-cells. The outcome is quite often injurious to the pathogens, with common sequelae of infected cells being killed.
There are two major classes of MHC molecules, each with their own specificities and functions. They both consist of two alpha- and beta-chains from different sources. MHC class I molecules consist of a heavy alpha-chain spanning the membrane, which is coded by MHC genes, while beta-chain is a light chain and is produced by the beta2-microglobulin gene.
The MHC class 1 molecule has three globular domains alpha 1 (yellow), alpha 2 (green) and alpha 3 (blue). The highly conserved α3 immunoglubilin-like domain is the binding site for CD8. (via Hunt, D.M. (2015). Immunology. In: Microbiology and Immunology On-line, Hunt, R.C. editor.http://www.microbiologybook.org/mhunt/flu.htm.)
MHC class II molecules contain 2 chains which span the membrane; they are both coded for by MHC genes.
MHC class II molecules comprise two non-identical peptides (alpha and beta) which are non-covalently associated and traverse the plasma membrane with the N terminus to the outside of the cell. (via Hunt, D.M. (2015). Immunology. In: Microbiology and Immunology On-line, Hunt, R.C. editor.http://www.microbiologybook.org/mhunt/flu.htm.)
Both MHC molecules consist of a groove which binds the peptides; it forms a complex, which enables them to be presented to T-cells. The groove is known as peptide-binding groove.
These molecules also play a major role in determining the success of transplantation. This is because transplanted cells can act just like regular antigens and stimulate an adaptive immune response. The MHC molecules are also often called the HLA complex, or human leukocyte complex, in the context of tissue matching.
MHC class I molecules are present on all nucleated body cells. They present those antigens that are present in the cellular cytoplasm. These can include foreign proteins, self-proteins, viral proteins and so on.
Once MHC class I molecules combine with antigenic peptides to be displayed on the cell surface, they mainly activate cytotoxic T-lymphocytes. Cytotoxic T-cells can then identify the potentially toxic cell and eliminate it. MHC molecules are basically part of the HLA antigen group. Those HLA antigens that correspond to MHC class I molecules include HLA-A, B and C.
Peptides from the cytosol associate with class I MHC and are recognized by Tc cells. Peptides from within vesicles associate with class II MHC and are recognized by Th cells.
MHC class II molecules are only present on antigen presenting cells. These include dendritic cells, macrophages and B-lymphocytes. These molecules are responsible for presenting antigens that are present extracellularly. This is done by phagocytosing the potentially harmful organism, degrading it, processing the antigen and then presenting it to T-cells.
Macrophages are stimulated to eliminate micro-organisms in their intracellular vesicles, and B-cells are stimulated to deliver antibodies that kill extracellular pathogens. Pathogens that manage to survive and thrive intracellularly (such as M. Tuberculosis), can proliferate in a manner that allows its escape from presentation by an MHC molecule.
Once these MHC class II molecules combine with antigens and are displayed on the surface of antigen-presenting cells, they activate T helper cells. As mentioned, HLA antigens are the MHC molecules. Those HLA antigens that correspond to MHC class II molecules include HLA-DP, DQ, DR, DM, DOA and DOB.
The different MHC proteins are coded by the MHC gene, which is located on chromosome 6. The initial part of the locus codes for MHC protein class II, while the latter part codes for MHC protein class I.
Polymorphism of MHC Molecules
Two separate properties of MHC make it impossible for pathogens to avoid it. To start with, MHC is polygenic: it contains a few distinctive MHC class I and MHC class II qualities so that each person has an arrangement of MHC molecules that have varying specificities for different peptides.
Second, MHC is profoundly polymorphic, i.e., there are multiple variants of every gene, giving rise to a magnificent diversity within the population. MHC qualities are, indeed, the most polymorphic qualities known.
Once the antigens are presented on the cellular surface, bound to the MHC molecules, they need to activate the T-cells as well. To ensure the attachment and action of these antigens, the T-cells possess TCRs. These receptors are specific for specific antigens and bind the antigen attached to the MHC molecules, stabilizing it. This allows the second messenger systems to come into play, which in turn activates the T-cells.
Two Pathways of Antigen Processing
The method of antigen processing occurs in two distinct ways. Obviously, as there are two distinct types of antigens being processed, their processing pathways must be different also. Here we describe the two pathways separately.
The endogenous pathway
This pathway is used for the MHC class I molecules which are associated with all the endogenous antigens. The process starts with ubiquitination of the endogenous antigens, which marks them for degradation by the proteasomes.
The proteasomes function to break these antigenic proteins into small peptides of about 8-9 amino acids long, which are, in turn, transported with the TAP into the endoplasmic reticulum. TAP, or Transporter associated with antigen processing is a member of the ATP-binding-cassette transporter family. It delivers cytosolic peptides into the endoplasmic reticulum (ER), where they bind to nascent MHC class I molecules.
At the same time, chaperone proteins within the rough endoplasmic reticulum help facilitate the proper folding of the MHC class I molecules and β2-microglobulin. These partially folded MHC class I molecules are then associated with TAP via another protein called tapasin. The molecules combine together and are then secreted from the cell by the Golgi apparatus, to be displayed on the cellular surface.
The exogenous pathway
This pathway is for the MHC class II molecules and is used by the antigen presenting cells. Initially, the proteins are phagocytosed and broken down by proteases in endosomes to peptides that are about 15 amino acids long.
In the rough endoplasmic reticulum (ER), the naïve MHC class II molecules (alpha and beta chains) associate with each other and a third protein, called the “invariant chain” which stabilizes the complex. Without the invariant chain, the alpha and beta proteins will not associate. The Invariant chain (Ii), which trimerizes in the ER, associates with MHC class II molecules and is released from the ER as a nine subunit complex. This MHC-invariant complex passes from the RER to, and out of, the Golgi body. Before moving to the cell surface, the vesicle containing this complex fuses with the endosome containing the antigen peptides. Here the invariant chain is proteolytically degraded and only a small part, called CLIP, remains attached to the peptide binding groove. The antigen peptide from the external protein associates with the MHC II molecule in the channel between the alpha-1 and beta-1 domains. Then another protein called HLA-DM removes CLIP and allows the chain to start attaching to the peptide. The resulting MHC II-peptide complex proceeds to the surface where it is expressed, ready for antigen presentation. MHC II molecules appear to be expressed on the surface of cells in pairs.
There is no clear differentiation between the endogenous and exogenous pathway. Peptides derived exogenously are presented via the MHC class I molecules. The cell begins the process by exogenous pathway but ends up diverting the antigens to the endogenous pathway; this allows the cell to skip some of the steps of the exogenous pathway.
As the exogenous pathway can involve infection before presenting the antigens, the cross-presentation allows the dendritic cells to process and present antigens without being infected.
This allows the antigens to stimulate different T-cells, the endogenous antigens stimulating the helper T-cells via class II molecules and the exogenous ones cross-stimulating the cytotoxic T-cells via the class I molecules. However, not every antigen presenting cell can utilize the ability to cross-present.
Presentation of Lipid Antigens by CD 1
Aside from the proteinaceous antigens, some cells also possess lipid antigens. These cannot be presented via the MHC molecules. For these antigens, the body employs the CD 1 molecules, which are a non-polymorphic family of glycoproteins that are capable of presenting lipid antigens to T-cells. The molecules have a unique binding structure that allows them to bind to and present a wide variety of lipid antigens.
The process starts by phagocytosis of the antigens into the cell; then, lipases degrade them into the smallest pieces. The CD 1 molecule is present in the endoplasmic reticulum. The small pieces of lipid antigens are mixed and bound with the CD 1 molecules, which are then exocytosed to the cell surface. There they present their antigens to the T-cells and the natural killer cells.
In short, the body has the capability of expressing both lipid and protein antigens. Our immune system is equipped to fight every foreign invader with complex and intricate processes that are nothing short of a miracle.