Major Histocompatibility Complex Structure, Function & Ligands

Major Histocompatibility Complex (MHC) Structure, Function & Ligands


  • Introduction
  • Main Histocompatibility Complex (MHC): what is it?
  • When was the MHC Complex discovered?
  • Structure of MHC Molecules
  • The function of MHC Molecules
  • Ligands for MHC Molecules
  • Antigen Presentation (AP)
  • Big Histocompatibility Complex: Why It Matters
  • The Major Histocompatibility Complex and Its Roles
  • Common Questions About Major Histocompatibility Complex
  • References


There is no biological system more important than the immune system. Its primary function is to shield the organism from potential dangers. Growing up in an environment free from outside influences is also beneficial. The immune system `wards off many dangers. It provides defense against a wide range of alien toxic substances. They are detected and eliminated. To ensure the animal’s healthy development during its formative years. The idea that white blood cells are the only building blocks of an immune system is widespread. That, however, is not an accurate assumption. Various components and proteins work together to form this comprehensive system. Identical substances are known as Major Histocompatibility Complexes (MHC).

Major Histocompatibility Complex (MHC) Structure, Function, and Ligands

Major Histocompatibility Complex (MHC): what is it?

The chemicals found on the surface of nucleated cells are MHC. Protein is the main ingredient. Almost every cell in the human body has the MHC. The brain’s neurons, however, lack these cells. The reason is that neurons lack a nucleus. Within each cell lies the MHC. Yet, it travels to the cell surface to perform an action if the body’s immune system is involved in a battle.

The MHC catalogs potentially harmful foreign chemicals to the body. Two kinds of foreign substances are possible. There is one that is associated with the bodily part and another that is unrelated to it at all. Living in harmony is signified by “compatibility,” while “histo” refers to the tissues. MHC was formed by combining these two terms.

T lymphocytes collaborate with the MHC. Foreign element signals are the sole things that the MHC supplies. The T cells’ job is to eliminate the invader. The kind of Major MHC also affected the T cells.

When was the MHC Complex discovered?

Immunologist Peter Gorer was the first to discover MHC in the 1930s. Not until the tissues were transplanted was this fact first noticed. They were mice that Peter Gorer was using in his experiments. Transplanting tissues from one mouse to another was his goal. During a tissue transplant, one organism’s cells or tissue are injected or transplanted into another. The ultimate goal of this investigation is organ transplantation.

Still, Peter Gorer sees something unusual while doing this experiment. Later on, he learned that the transplanted mice had perished. With that in mind, he chose to alter the course of the experiment. He rounded up a litter of mice. Additionally, he does tissue transplants on each of those pairs. These two sets of mice are really from distinct species of mice. Following in the footsteps of the preceding group, one behaves similarly. At last, one set of mice crossed across. Additionally, there is a different class that manages to stay alive.

Based on his findings, he concludes that some tissues contain an foreign substance that confuses certain mice. Nothing like that happens with other mice. It turns out that the compounds killing the mice are indeed MHCs. Our own MHCs are present as well. Thus, verifying all the factors before undergoing organ transplantation is essential.

MHC plays a key role in the immune response of vertebrates, including humans. The MHC is a set of genes that encode cell surface proteins responsible for regulating the human immune system.

Structure of MHC Molecules:

MHC molecules are divided into classes: Class I and II, each with a distinct structure and function.

  • MHC Class I: These molecules are found on the surface of nearly all nucleated cells. They comprise a heavy chain (α chain) non-covalently associated with a smaller protein called β2-microglobulin. The heavy chain of MHC Class I has three domains (α1, α2, and α3), with the peptide-binding groove being formed by the α1 and α2 domains.

The MHC Class I major histocompatibility complex
With the exception of nerve tissues and platelets, all nucleated cells include MHC Class I.
Class I MHC molecules are 45 KD in size. A category of important histocompatibility antigens is this.
Its functionality was limited to T cells alone. Foreign materials are helped to destruction by these T cells.
The cell-mediated immune response is the only one it can activate. It remains dormant until such a reaction occurs.
It has the ability to attach to T cells via their CD-8 adhesion molecule.
Class I of the Major Histocompatibility Complex has three different kinds of HLA genes.
Endogenous antigens bind to MHC Class I.

Building Blocks of the MHC Class I Subunit
There is nothing complicated about the MHC Class I structure. It reminds us of a chain. On its whole, the building resembles a chain. In structure, it resembles RNA. There is a link in the chain that extends into the cell membrane. The MHC Class I structure is formed at the opposite end. Three primary folds can be seen on the structure. They are all constructed from a single chain bent.

In this case, we have two chains. As an example, there is the Alpha chain and the Beta chain. Their structure is a polypeptide chain. For alpha, there are three distinct domains. Alpha, Alpha2, and Alpha3 are their numbers. In the Beta, there is only one domain. No longer is the beta attached to the cell membrane in any way. Each Alpha domain is a link in the chain that binds to a membrane.

The Beta is non-covalently bound to the Alpha chain. Beta domains also include transmembrane glycoproteins. They serve as the human leukemia antigen gene. In the Alpha2 and Beta domains, you may find two di-sulfate compounds. There, they cement the connection.

  • MHC Class II: These molecules are primarily expressed on antigen-presenting cells such as dendritic cells, macrophages, and B cells. MHC Class II molecules consist of two similar-sized chains, an α chain and a β chain, each contributing to the formation of the peptide-binding groove with its α1 and β1 domains, respectively.

Class II Major Histocompatibility Complex
The cells that carry antigens include these substances. The cells whose main function is to eliminate pathogens fall under this category.
It firmly attaches to the foreign cells. This refers to cells that originate entirely from outside the body.
Th cells are the only ones it attaches to. Only MHC Class II responses can be recognized by this type of T cell.
All members of MHC class II share a single gene type. Those are the basic HLA types.
The kind of chain determines the size of MHC Class II cells. The size may be adjusted according to the kind of chain.
Only when an outside element gets inside a cell can it leave the cell.

The Class II Major Histocompatibility Complex and Its Structure
In general, two kinds of chains are present. A beta and an alpha chain exist. However, the framework differs from that of Class I. Two chains attach themselves here within the cell membrane. The cell membrane contacts both chains on one side. The other side constructs the building. Two distinct modifications have taken place. Such chains form many domains.

Due to the Alpha chain, two domains will be generated. Alpha1 and Alpha2 are their names. Two distinct domains will be produced by the beta chain as well. There is Beta1 and Beta2. The non-covalent bonding will bind all the chains together. The domain contains di-sulfate bonds. The di-sulfate bond is present in all domains, with the exception of the Alpha2 domain. Because of this connection, the domain can maintain its shape. The combination of Alpha1 and Beta1 will create the peptide binding site. Attached to this spot is the foreign material. Consequently, the T Helper cells will get the signal to eliminate the contaminants.

The function of MHC Molecules:

  • Antigen Presentation: The primary function of MHC molecules is to present peptide fragments derived from pathogens to T cells. MHC Class I presents peptides to CD8+ cytotoxic T cells, and MHC Class II presents peptides to CD4+ helper T cells. This presentation is crucial for T cell receptor (TCR) recognition and the activation of T cells.
  • Self vs. Non-self Discrimination: MHC molecules help the immune system distinguish between self and non-self. MHC molecules present the body’s own proteins without triggering an immune response, establishing tolerance to self-antigens. Non-self antigens, such as those from pathogens, are recognized as foreign, leading to an immune response.

Ligands for MHC Molecules:

  • MHC Class I Ligands: These are typically 8-10 amino acids in length and consist of endogenous peptides generated within the cell’s cytoplasm. These peptides are produced from the degradation of cellular proteins by the proteasome, then transported into the endoplasmic reticulum by the transporter associated with antigen processing (TAP) and loaded onto MHC Class I molecules.
  • MHC Class II Ligands: These are generally 13-18 amino acids long and contain exogenous peptides originating outside the cell. Antigens are taken up by antigen-presenting cells through endocytosis or phagocytosis, processed in endosomes and lysosomes, then loaded onto MHC Class II molecules within specialized compartments known as MIIC (MHC Class II compartments).

Once peptide-MHC complexes are displayed on the cell surface, they can be recognized by the TCR on T cells, leading to immune activation. The diversity of MHC gene variants in the population is extensive, which contributes to the ability of the human immune system to respond to a vast array of pathogens. However, this diversity also underlies individual differences in disease susceptibility and response to transplantation and immunotherapy.

Antigen Presentation (AP)

The MHC mostly contains one kind of antigen. Human Leukocyte Antigens, or HLAs, are what they are. This is the MHC’s primary motivation. A wide variety of HLA are in existence. Three different kinds of HLAs make up MHC Class I. They are known as HLA-A, HLA-B, and HLA-C. There are three different kinds of HLAs in MHC Class II. Their names are HLA-DR, HLA-DQ, and HLA-DP.

To better detect invaders, the HLA plays a role. Within the body, you’ll find cells of every kind. Because nucleated cells are the only ones that display MHC Class I. Thus, a recognition process is required to identify the correct substance. The HLA does something similar. The sort of foreign material was the first thing it could identify. If the elopement originates in the body, the signal is sent to MHC Class I by the appropriate HLA. When an element is not naturally occurring, the HLA signals MHC Class II. They proceed to carry out their routine tasks there.

Big Histocompatibility Complex: Why It Matters

An essential component of the human body is the MHC. Knowing what might harm our immune system is helpful. Disposing of an invader is an important responsibility whenever one enters the body. However, this is not limited to WBCs. Some compounds are associated with vital functions in our bodies. Those things should remain unchanged. Foreign objects and essential substances must be distinguished. The MHC performs that function.

The format of the MHCs’ reaction might change depending on the scenario. Do not mistake them for antibodies. They aren’t interacting with the outside forces directly. They may identify the element. It follows that the T lymphocyte cells get a singular, important message. The destruction of the elements will be carried out by these cells. The MHCs’ only function is to ensure that the T cells get accurate messages. After that, these cells will affect those cells. At times, the survival of other cells depends on the cell’s demise. Sometimes, it may be sufficient to eliminate only the alien component.

It would be challenging for the body to identify foreign materials if MHCs are absent. Consequently, such components won’t be able to be destroyed. That has the potential to do serious harm to the body. Additionally, our bodies benefit from certain elements. Removing such compounds from our bodies will cause greater responses. The MHCs are, therefore, the primary conveyors of messages to the alien element destroyers.

Major Histocompatibility Complex and Its Roles

To aid the immune system is the primary role of the MHC. It is not possible for T Lymphocytes to identify possible dangers to the body. Primarily, MHCs identify danger to the body and send a signal to eliminate it.
T lymphocytes are directed to eliminate foreign substances inside the body via the MHC. It attaches to the element in accordance with the foreign element’s categorization. Subsequently, it instructs the T lymphocyte cell to eliminate it. And finally, it’s ruined.
Binding to peptide epitopes is a common occurrence for MHC molecules. Ligands for TCRs are produced as a result of this. The redistribution of tissues will be aided once again by this ligand. It is also possible to do this using T cells. Following cell breakdown, ligands aid in reassembling the cell to its original shape.

Common Questions About Major Histocompatibility Complex

1. To begin, when and who were the MHCs invented?


The MHCs were developed in 1930 by scientist Peter Gorer. He tested his hypothesis using mice. Consequently, he obtained a pair of MHCs. Subsequent research confirmed that MHCs are intrinsic to all vertebrates.

2. My second question is: what exactly is HLA?


Human Leukocyte Antigen is the complete name of this gene. In MHCs, they serve as a specialized gene. Because the MHCs contain the HLA. The MHCs are sometimes called HLAs as well. Thus, the same item may be defined by both the HLA and the MHC.

3. The third question is, how big are MHC Class II peptides on the alpha and beta chains?


The alpha chain peptides are 33 kD in size. Finally, the beta chain peptides measure 28 kD. Considering the dissimilarity between these two chains. Additionally, the chains’ peptide sizes vary.

4. Fourth Question: Which MHC class II protein is the peptide binding cleft located?


Classes I and II of the MHC include peptide-binding clefts. In MHC Class II, the Alpha1 and Beta1 domains form this peptide binding cleft. The T cells are signaled by foreign particles bound to this cleft.

5. Question five: Are MHCs present in neurons?


No. To put it simply, neurons lack MHCs. The MHCs can only be present in cells that contain a nucleus. Among MHC classes, only Class II is nuclear-independent. However, only some cells have access to them. Consequently, the neurons do not have any MHCs.


Deeg, Janosch. (2014). Modulation of T cell Activation with Nano- and Micronanopatterned Antigen Arrays.

Lin, A. and K. Loré (2017). “Granulocytes: New Members of the Antigen-Presenting Cell Family.” Frontiers in Immunology 8.

Dr AF Saeed

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