The Class I & II Major
Histocompatibility Complexes

MHC Class I is a membrane spanning molecule composed of two proteins.

The spanning protein is approximately 350 Amino Acids in length, with approximately 70 Amino Acids at the Carboxylic end, comprising the TransMembrane and cytoplasmic portions.

The remaining 270 Amino Acids are divided into three Globular domains labeled alpha-1, alpha-2 and alpha-3 prime.

With alpha-1 being closest to the Amino terminus and alpha-3 closest to the membrane.

The second portion of the molecule is a small Globular protein called beta-2 MicroGlobulin. It associates primarily with the alpha-3 prime domain and is necessary for MHC stability.

Though similar to Class I molecules, MHC Class II is composed of two membrane spanning proteins.

Each of these proteins is approximately 30 KiloDaltons in size, and made of two Globular domains.

The domains are named alpha-1, alpha-2, beta-1 and beta-2.

The two regions farthest from the membrane are alpha-1 and beta-1. The two proteins associate without Covalent Bonds.

In humans, the MHC I and II Genes are located at separate, but nearby loci on the Sixth Chromosome.

The Class I locus contains three smaller loci of Genes for three distinct Class I Genes, named A, B and C.

All code for Class I molecules, but each is distinct in its structure and binding capacity. Every human possesses at least one version of A, B and C Class I molecules.

Since an individual gains one strand of DNA from each parent, most people have two distinct variants of A, two of B and two of C, for a total of six distinct MHC I Genes.

The Class I Gene codes only for the alpha protein of the Class I molecule. The beta-2 MicroGlobulin Gene is very constant and is located elsewhere in the Genome.

A similar situation exists for MHC II, where the locus is split into three smaller loci named DP, DQ and DR.

Again, most people have two variants of each, for a total of six MHC II Genes. Each Gene codes for a variant of both the alpha and beta protein.

Since it is possible for an alpha unit from one Gene to associate with a beta of another, there are a maximum of twelve different MHC II molecules.

The prevelance of different HLA types vary widely in different populations.

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MHC & Peptide Processing

Internal MHC I

A small percentage of all the proteins inside the Cytosol of a cell are degraded by a Low Molecular Weight Protease (LMP).

They are then, moved from the CytoPlasm to the Rough Endoplasmic Reticulum(RER), by the Transporter of Antigenic Peptide (TAP) protein.

Inside the RER some of these Peptides, which are approximately ten Amino Acids in length, will associate with the alpha-1 and alpha-2 proteins of MHC Class I.

The Peptide must bind to the cleft, between the alpha-1 and alpha-2 domains of the molecule, and produce a change in shape.

This allows for the association of the beta-2 MicroGlobulin, or the MHC molecule will destabilize and not be expressed on the cell surface.

Peptides which meet this requirement form a complex with the MHC Class I molecule. This complex is transported in a Vesicle from the RER to the Golgi Body and from there to the surface of the cell.

With the exception of Neurons, all Somatic Nucleated Cells express MHC Class I on their surfaces.

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Exogenous MHC II

The MHC Class II molecule primarily presents Peptides, which have been digested from external sources.

Since only Antigen Presenting Cells (APCs) digest foreign protein, these are the only cells which normally express MHC II on their surface.

The path toward the surface of a cell is somewhat different for a Class II molecule.

Within the RER the alpha and beta proteins of the molecule, associate with each other, and a third protein called the "invariant chain," which stabilizes the complex.

In the absence of the invariant chain, the alpha and beta proteins will not associate. The MHC-invariant complex is then passed from the RER, into and out of, the Golgi body.

Before it proceeds to the surface of the cell, the vesicle which contains the complex, fuses with an Endocytic compartment, where an external protein has been sampled and degraded.

In this compartment, the invariant chain is destroyed and part of the degraded protein associates with the MHC II molecule, in the cleft between the alpha-1 and beta-1 domains.

The resulting MHC II-Peptide complex, proceeds to the surface where it is expressed. MHC II molecules are expressed on the surface of cells in pairs.

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Exogenous MHC I

Though the exact mechanism has yet to be determined, it is possible for certain APCs to ingest and degrade proteins, and associate them with MHC I molecules.

This pathway is of particular interest for the developers of vaccines, who wish to induce a T-Cell response by inoculation with Exogenous Peptides.

MHC I / T-Cell Interactions

Most Cytotoxic T-Lymphocytes (CD8⁺ Cells) possess both T-Cell Receptors (TCR) and CD8⁺ molecules (as well as many other proteins) on their surfaces.

These TCRs are able to recognize Peptides, but only when they are expressed in complexes with MHC I molecules. In order for the TCR to bind a Peptide-MHC complex two requirements must be met:

• The TCR must have a structure which allows it to bind the Peptide-MHC complex

• The accessory molecule CD8⁺, must bind to the alpha-3 domain of the MHC Class I molecule

Due to Genetic recombination events, each T-Cell expresses a unique TCR, which will only bind a specific MHC-Peptide complex.

T-Cells that recognize Self-Peptides are eliminated in the Thymus or Tolerized by an unknown mechanism, after their release from the Thymus.

As a result, if a T-Cell is able to bind to a MHC-Peptide complex on the surface of a cell, this cell is producing a Peptide which is not native to the person.

If this occurs, the CD8⁺ Cell separates from the invaded cell, grows (differentiate), and divides (Colonal Expansion).

This, and the subsequent development into a mature CD8⁺ Cell, requires more Cytokines (notably, InterLeukin-2 from CD4⁺ Cells).

However once differentiated, the T-Cell and its progeny will eliminate any cells expressing the same Peptide-MHC complex, which activated the original CD8⁺ Cell.

In addition, some of the progeny will become dormant Memory T-Cells. Though poorly understood, these cells stay in a resting state, until encountering the Peptide-MHC complex they recognize (e.g. during a re-infection with the same Antigen), whereupon they become mature CD8⁺ Cells.

The MHC I molecule acts as a means of assuring that self cells, have not been compromized by infection or mutation.

Any cell which is hosting a Virus or manufacturing mutant proteins (as in the case of Cancer) will present these foreign Peptides upon its surface. A CD8⁺ Cell will recognize them and eventually the cell will be destroyed.

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MHC II / Helper T-Cell Interactions

The Helper T-Cells (CD4⁺ aka [Th Cell]) is responsible for regulating almost every Acquired Immune System activity.

The signaling molecules on its membrane and the Cytokines it produces are necessary for the development of most Acquired Immune Responses.

Just as CD8⁺ Cells must interact with MHC I, Helper T-Cells must contact a MHC II-Peptide complex, which they recognize, in order to be activated. Instead of CD8, Helper T-Cells, have a molecule called CD4, which binds to MHC II.

As in the case of CD8⁺ Cells, self-reactive cells are destroyed in the Thymus or Tolerized in the periphery, so if a Peptide is recognized, it is probably of foreign origin.

Assuming the APC which presented the MHC II-Peptide, also possessed a surface molecule or Cytokine which acted to co-stimulate the CD4⁺, the cell will produce Cytokines to allow its own maturation and propagation.

These CD4⁺ Cells will then proceed to supply the necessary Cytokines for Immune Responses against Antigen they recognize. Both Humoral and Cytotoxic Immunity are seriously hindered without this support.

In some cases, as in the Immune Response to Tuberculosis, the CD4⁺ Cells activation of the Innate Immune System is the Primary Immune Response.

As with CD8⁺ Cells, a portion of CD4⁺ Cells are Memory Cells, which remain dormant until a reinfection occurs.

The importance of the T-Cell in the Immune System, particularly regarding IntraCellular Infections and Tumors is clear.

The MHC molecules appear to be the keys to understanding and manipulating both CD4⁺ and CD8⁺ Cells.

Though our understanding of the TCR is limited, we have a great deal of knowledge concerning the presentation of Peptides by MHC molecules.

A reliable method for predicting Peptides that can bind to MHC and may be able to induce T-Cell Immunity, will be of great value.

Newer techniques will improve our understanding of T-Cells and Immunity.

With that improvement will come an ability to develop superior means of modulating Immune Responses.