MHC Molecules and Antigen Presentation

Antigen Presentation to T Lymphocytes and MHC Molecules

T lymphocytes identify peptide fragments of protein antigens presented on host cell surfaces via Major Histocompatibility Complex (MHC) molecules.
T cell-mediated immune responses target protein antigens made or absorbed by host cells, allowing T cells to find intracellular foreign antigens.

Antigens Recognized by T Lymphocytes

T cells identify peptide antigens attached to MHC molecules on antigen-presenting cells (APCs).
MHC molecules function as peptide display molecules in the immune system.
T cells exhibit MHC restriction, identifying peptides solely when presented by their own MHC molecules.
The T cell receptor (TCR) identifies amino acid residues of the peptide antigen and polymorphic residues of the MHC molecule.
Certain T cells identify lipid and nonpeptide antigens presented by class I MHC-like molecules or without a specialized display system.
Antigen-presenting cells (APCs) capture microbial antigens and present them for T lymphocyte recognition.
Naive T lymphocytes are triggered by dendritic cells, leading to clonal expansion and differentiation into effector and memory cells.
Effector T cells are triggered by various APCs, including dendritic cells, to perform their effector functions in humoral and cell-mediated immune responses.

Capture of Protein Antigens by Antigen-Presenting Cells

Protein antigens are mainly captured by dendritic cells and concentrated in secondary lymphoid organs.
Antigens are transported to secondary lymphoid organs via:
- Dendritic cells capturing antigens in tissues and transporting them to lymph nodes.
- Microbes or antigens carried in lymph or blood and captured by resident dendritic cells in lymphoid organs.
Dendritic cells in epithelia and tissues capture microbial antigens.
Conventional dendritic cells capture and present most protein antigens to T lymphocytes.
Plasmacytoid dendritic cells are a major source of type I interferons in response to viral infections.
Dendritic cells bind microbes using membrane receptors, taking them up via phagocytosis or receptor-mediated endocytosis.
Microbial products stimulate innate immune reactions via Toll-like receptors (TLRs) and other pattern-recognition receptors.
Inflammatory cytokines, such as TNF and IL-1, are produced, activating the dendritic cells and altering their phenotype, migration, and function.
Activated dendritic cells lose adhesiveness for epithelia, express CCR7, and migrate to lymph nodes.
During migration, dendritic cells mature into APCs capable of stimulating naive T lymphocytes, reflected in increased MHC molecule and costimulator expression.
Naive T lymphocytes continuously recirculate through lymph nodes and express CCR7, promoting their entry into T cell zones.

Functions of Different APCs

Dendritic cells:
- Induce T-dependent responses.
- Located at microbe entry sites.
- Migrate to lymph nodes.
- Potent activators of naive T lymphocytes due to high levels of MHC molecules and costimulators.
Macrophages:
- Important for effector T cells, especially helper T cells.
- Phagocytose microbes and present antigens to effector T cells.
- Reactivated to kill ingested microbes in cell-mediated immune reactions.
B lymphocytes:
- Endocytose protein antigens and display them to helper T cells.
- Essential for humoral immune responses to protein antigens.
Nucleated cells:
- Present peptides derived from foreign protein antigens in the cytosol to CD8+ effector T cells.

Structure and Function of Major Histocompatibility Complex Molecules

MHC genes determine the acceptance or rejection of tissue grafts.
The physiological role of MHC molecules is to display peptides derived from microbial protein antigens to antigen-specific T lymphocytes.
MHC molecules explain the phenomenon of MHC restriction of T cells.
All vertebrates possess maternally and paternally inherited MHC loci.
Human MHC molecules are called human leukocyte antigens (HLAs).
MHC contains two sets of highly polymorphic genes: class I and class II MHC genes.
MHC also contains many nonpolymorphic genes involved in antigen presentation.

Structure of MHC Molecules

Class I and class II MHC molecules are membrane proteins with extracellular peptide-binding clefts.

Class I MHC Molecules

Composed of an α chain noncovalently associated with β2-microglobulin (encoded outside the MHC locus).
- The α chain has three extracellular domains, transmembrane and cytoplasmic domains.
- α1 and α2 domains form the peptide-binding cleft, accommodating peptides of 8 to 11 amino acids.
- Polymorphic residues are in the α1 and α2 domains, influencing the ability to bind distinct sets of peptides.
- The α3 domain is invariant, associates with β2-microglobulin, and binds the CD8 T cell coreceptor.
- CD8+ T cells respond to peptides displayed by class I MHC molecules.

Class II MHC Molecules

Composed of two transmembrane chains, α and β, each with two extracellular domains, transmembrane and cytoplasmic regions.
- α1 and β1 domains contain polymorphic residues and form a cleft accommodating peptides of 10 to 30 residues.
- Nonpolymorphic α2 and β2 domains contain the binding site for the CD4 T cell coreceptor.
- CD4+ T cells respond to peptides presented by class II MHC molecules.

Properties of MHC Genes and Proteins

Polymorphism: Many different alleles are present in the population.
- Ensures that some individuals can present peptides from any microbial protein antigen.
- The total number of different HLA proteins in the population is estimated to be more than 18,000 with about 13,000 class I and 5400 class II polypeptides.
Codominant expression: Alleles inherited from both parents are expressed equally.
- Maximizes the number of HLA proteins expressed, enabling the display of a large number of peptides.
Expression patterns: Class I molecules are on all nucleated cells, while class II molecules are mainly on dendritic cells, macrophages, and B lymphocytes.

Inheritance Patterns and Nomenclature of HLA Genes

Humans have three polymorphic class I genes: HLA-A, HLA-B, and HLA-C.
Individuals inherit genes encoding the α and β chains of DP and DQ, the gene for DRα, and variable numbers of genes encoding DRβ.
The set of MHC genes on each chromosome is called an MHC haplotype, inherited together in a Mendelian fashion.
Each HLA allele is given a numeric designation, e.g., HLA-A2, B5, DR3.

Peptide Binding to MHC Molecules

Peptide-binding clefts of MHC molecules bind peptides derived from protein antigens.
Anchor residues in peptide antigens fit into pockets in MHC molecules, anchoring peptides in the cleft.
Other residues project upward and are recognized by the antigen receptors of T cells.
Each MHC molecule can present only one peptide at a time but can present many different peptides.
Peptides must have the optimal length and amino acid sequence for MHC binding.
MHC molecules bind mainly peptides due to their structural and charge characteristics.
MHC molecules acquire peptide cargo during biosynthesis, assembly, and transport inside cells.
Only peptide-loaded MHC molecules are stably expressed on cell surfaces.
MHC molecules display peptides derived from self and foreign proteins.
T cells specific for self-antigens are eliminated or inactivated to prevent autoimmune responses.

Processing and Presentation of Protein Antigens

Peptide fragments of proteins are displayed by class I MHC molecules in any nucleated cell, while in specialized APCs proteins are displayed by class II MHC molecules.
Class I MHC pathway: Proteasomal processing of proteins in the cytosol.
Class II MHC pathway: Endosomal/lysosomal processing of proteins derived from the extracellular environment.

Processing of Cytosolic Antigens for Display by Class I MHC Molecules

Steps:
1. Tagging of antigens in the cytosol or nucleus for proteolysis.
2. Proteolytic generation of peptide fragments by the proteasome.
3. Transport of peptides into the endoplasmic reticulum (ER).
4. Binding of peptides to newly synthesized class I molecules.
5. Transport of peptide-MHC complexes to the cell surface.
Proteasomes degrade misfolded proteins into peptides.
Proteins are unfolded, tagged with ubiquitin, and threaded through the proteasome.
The enzymatic composition of proteasomes changes with exposure to inflammatory cytokines, becoming efficient at cleaving proteins into peptides that bind well to class I MHC molecules.
TAP transports proteasome-generated peptides into the ER.
Newly synthesized class I MHC molecules associate with tapasin, linking them to TAP molecules.
High-affinity peptide loading stabilizes class I MHC molecules, which are then exported to the cell surface.
Viruses block the class I MHC pathway to evade the adaptive immune system.

Cross-Presentation of Internalized Antigens to CD8+ T Cells

Some dendritic cells can present ingested antigens on class I MHC molecules to CD8+ T lymphocytes.
Dendritic cells can ingest infected host cells, dead tumor cells, microbes, and microbial and tumor antigens, and transport them into the cytosol.
Antigenic peptides are generated, enter the ER, and bind to class I molecules.
This process is called cross-presentation or cross-priming.
CTLs kill infected host cells or tumor cells upon antigen recognition.

Processing of Internalized Antigens for Display by Class II MHC Molecules

Steps:
1. Internalization of the antigen.
2. Proteolysis in endocytic vesicles.
3. Association of peptides with class II molecules.
4. Transport of peptide-MHC complexes to the cell surface.
Antigens destined for the class II MHC pathway are internalized from the extracellular environment.
Microbes bind to surface receptors or receptors for opsonins, and B lymphocytes internalize proteins binding to their antigen receptors.
Microbial proteins enter acidic intracellular vesicles (endosomes or phagosomes), which fuse with lysosomes, where proteins are broken down by proteolytic enzymes.
Class II MHC molecules carry an invariant chain (Ii), including a class II invariant chain peptide (CLIP), that binds to the peptide-binding cleft.
The class II molecule with its associated Ii migrates to the membranes of acidic vesicles.
In this compartment, the invariant chain is degraded, leaving only CLIP in the peptide-binding cleft.
Vesicles contain DM, which exchanges CLIP for other peptides that can bind with higher affinity.
Peptide loading stabilizes class II MHC molecules, then it is exported to the cell surface.

Physiologic Significance of MHC-Associated Antigen Presentation

Restriction of T cell recognition to MHC-associated peptides ensures T cells respond only to cell-associated antigens thus intracellular microbes and extracellular environment.
The segregation of the class I and class II pathways enables the immune system to respond to extracellular and intracellular microbes in specialized ways.
Structural constraints on peptide binding to different MHC molecules account for the immunodominance of some peptides and the inability of some individuals to respond to certain protein antigens.

Functions of Antigen-Presenting Cells in Addition to Antigen Display

APCs express additional signals for T cell activation in response to microbes.
Antigen = signal 1 and APCs reacting to microbes = signal 2.
APCs express costimulators and secrete cytokines upon reacting to microbial products.

Antigen Recognition by Other T Lymphocytes

Natural killer T cells (NK-T cells) are specific for lipids displayed by class I-like CD1 molecules.
Mucosal associated invariant T cells (MAIT cells) are specific for bacteria-derived vitamin B metabolites displayed by class I-like MR1 molecules.
γδ T cells recognize a wide variety of molecules.

Summary

Induction of immune responses depends on capturing and displaying antigens for recognition by T cells.
MHC molecules display peptides derived from protein antigens.
MHC genes are highly polymorphic, expressing class I and class II MHC molecules.
Proteins in the cytosol are degraded by proteasomes, transported into the ER by TAP, bind to class I MHC molecules, and are displayed on the cell surface.
Proteins ingested from the extracellular environment are proteolytically degraded in vesicles, bound to class II MHC molecules, and displayed on the cell surface.
MHC molecules ensure that T cells recognize only cell-associated protein antigens.
Microbes activate APCs to express costimulators and secrete cytokines, providing signals for specific T cells.

Major Histocompatibility Complex (MHC) - Antigen Processing and Presentation

Learning Outcomes:
- Describe the structure of MHC class I and class II molecules.
- Explain MHC class I and class II antigen processing pathways.
- Compare and contrast MHC class I and class II processing, highlighting similarities and differences.
- Define the genetic underpinnings of MHC.
- Understand MHC restriction.
- Appreciate the clinical importance of MHC.

Recognizing Pathogens

The body needs to sense when a pathogen has invaded to eliminate it.
Pathogen recognition occurs through:
- Innate recognition
- B cell recognition
- T cell recognition

T Cell Receptor

T lymphocytes (T cells) are key cells of the adaptive immune response.
- T Helper cells (TH cells, CD4+ T cells)
- Cytotoxic T cells (killer T cells, CD8+ T cells)
T cells recognize the presence of pathogens indirectly.
The T cell receptor (TCR) recognizes peptides presented in MHC molecules.
The TCR needs to recognize the MHC molecule as part of pathogen recognition; recognition of both peptide and MHC results in strong binding.
The TCR is made in the thymus and is generated through a somewhat random process.
The TCR needs to be assessed before it leaves the thymus to ensure it recognizes an MHC molecule.

Major Histocompatibility Complex (MHC)

The Major Histocompatibility Complex (MHC) is the molecule that shows T cells a pathogen.
MHC molecules are membrane proteins that bind and present fragments of pathogens to T cells.
There are two types (classes) of MHC, but they both do the same thing – show pathogens to T cells.

T Cell Receptor Interaction with MHC

There are two classes of MHC, each of which presents antigens to the two major types of T cells.
T cell receptors are generated in the thymus randomly.
The T cell receptor interacts with peptide:MHC.
The T cell can’t function until it has been activated.
Activation requires three signals.

T Cell Activation

Three signals are required for T cell activation:
1. Peptide:MHC
2. Co-stimulation
3. Cytokines

MHC Classes

There are two classes of MHC, each of which presents antigens to the two major types of T cells.
- MHC class I presents to CD8+ T cells (cytotoxic T cells).
- MHC class II presents to CD4+ T cells (helper T cells).
Structurally similar, they differ in cell distribution and how they create peptide antigens for presentation.

MHC Pathway

MHC shows pathogen pieces (peptide) to the T cell.
For a pathogen to become a peptide, it needs to be fragmented.
The MHC pathway is the process where a pathogen is chopped up, loaded into an MHC molecule, and transported to the cell surface to interact with a T cell.

MHC Lecture Pathway

MHC class I and class II structure and expression
MHC class II pathway
MHC class I pathway
Genetics of MHC
MHC and T cell restriction
Clinical relevance of MHC

MHC Basic Structure

MHC class I and class II molecules have a similar structure:
- Transmembrane domain(s)
- Invariant domain
- Peptide binding pocket

Binding Pocket of MHC

The binding pocket binds peptides; this is one of the critical interactions required to activate a T cell.
The binding pocket can only bind one peptide at a time.
Many different peptides can ‘fit’ in the binding pocket.
This binding is very stable so that T cells have time to interact with the peptide:MHC.
MHC molecules are only stable when peptide is bound.

Cellular Expression of MHC Class I and Class II

MHC class I and class II are expressed on the surface of different types of cells.
MHC class I molecules are found on all nucleated cells.
- Present to cytotoxic T cells that kill virally infected cells.
- Viruses can infect any cell; therefore, every cell needs to be able to communicate an infection to cytotoxic T cells.
MHC class II is expressed on antigen-presenting cells (APCs); this includes:
- Dendritic cells
- Macrophages
- B cells
- Some other specialized cells

MHC Expression and Natural Killer Cells

MHC class I and class II molecules are expressed constitutively (i.e., all the time).
Cells not expressing MHC class I look ‘wrong’ to the immune system.
- T cells can only respond to a pathogen it can recognize in an MHC molecule.
- Some pathogens try to hide from T cells by down-regulating (reducing the expression) of MHC.
Cells not expressing MHC class I will be attacked by natural killer cells (and will die).

MHC Class II - Pathogen

MHC class II processes and presents peptide antigens from pathogens outside of the cell.
These pathogens or antigens are internalized (e.g., by phagocytosis).
Some examples include:
- Extracellular bacteria
- Extracellular fungi
- Anything

MHC Class II – Overview

Pathogens are ingested
Pathogens are degraded into peptides in an endosome
MHC class II leaves the ER in a vesicle that joins with the antigen-containing endosome
Peptide:MHC is transported to the cell surface

MHC Class II Processing Pathway

Extracellular pathogens
Degraded in lysosome
Peptide and MHC form a complex in vesicles
The peptide:MHC complex is exported to the cell surface
Presentation to CD4+ Helper T cell

MHC Class I - Pathogen

MHC class I processes and presents peptide antigens from pathogens (antigens) found in the cytosol.
This includes:
- Viruses that infect cells
- Obligate intracellular bacteria
- Extracellular bacteria that inject proteins into the cytosol
- Proteins ingested (phagocytosed) and released into the cytosol

MHC Class I Pathway – Overview

Pathogens found inside the cell or ingested and moved to the cytosol
Proteins are ‘tagged’ and degraded
Pushed into the ER where a new MHC class I molecule is waiting
Peptide:MHC is transported to the cell surface

MHC Class I Pathway

Cytosolic protein
Proteasome
TAP
MHC binds peptide
Transport to the cell surface
Expression on the cell surface
CD8+ Cytotoxic T cell
Antigen processing

MHC Class I Processing Pathway

Cytosolic pathogens
Ubiquinated and degraded in proteasome
Peptide and MHC form a complex in the ER
The peptide:MHC complex is exported to the cell surface
Presentation to CD8+ Cytotoxic T cell

MHC Class I – Cross Presentation

MHC class I processes and presents peptide antigens from pathogens (antigens) found in the cytosol.
- Viruses that infect cells
- Obligate intracellular bacteria
- Extracellular bacteria that inject proteins into the cytosol
- Proteins ingested (phagocytosed) and released into the cytosol
T cells need to be activated by a dendritic cell
If a dendritic cell isn’t infected by a virus, how can it process and present antigens from that virus? How can it express co-stimulatory molecules, and how does it secrete cytokines to stimulate an immune response?
MHC Class I – Cross Presentation
A virally infected cell (unless it is a dendritic cell) cannot activate a naïve T cell
Some dendritic cells can phagocytose infected cells, microbes, and microbial antigens
Some dendritic cells can phagocytose infected cells, microbes and microbial antigens and transport these to the cytosol. This allows the DC to present all three activatory signals to activate a naïve T cell.
The now activated T cell can discover and kill infected cells because they are expressing viral peptides in MHC class I molecules.
Cross presentation allows dendritic cells that have not been infected with a virus to process and present antigens from that virus, allowing that dendritic cell to present viral antigens in MHC class I molecules, upregulate co-stimulatory molecules, and secrete cytokines to stimulate a cytotoxic T cell response.

Genetics – A Brief Reminder

Gene – transcribed to make a protein
Allele – variations for a particular gene
- Polymorphic – a gene is polymorphic if there are two (or more) alleles for a gene
Phenotype – the expression of a gene (or genes)
Polygenic – two (or more) genes contribute to a phenotype
Haplotype – genes (alleles) inherited together
DNA –> RNA –> Amino acid chain –> Protein

The Genetics of MHC

There are two classes of MHC, and each presents peptide antigens to the two major T cell subsets
The binding pocket of MHC, where peptides bind, can bind many different peptide antigens (although only one at a time)
During the peptide generation phase of the MHC processing pathway, many peptides from any pathogen are made; hopefully, one of these peptides can bind the relevant MHC molecule
If none of the peptides bind, then T cells wouldn’t be able to mount an immune response against that pathogen
To solve this issue, during our evolution, we have duplicated the MHC genes
Instead of one MHC class I molecule being produced, we have six
- Three per chromosome
Instead of one MHC class II molecule being produced, we have six (or eight)
- Three per chromosome
- (Actually, three alpha chains per chromosome and three beta chains)

MHC is Polygenic

Three genes encoding (essentially) the same protein
- HLA-A
- HLA-B
- HLA-C
- HLA-DR
- HLA-DQ
- HLA-DP
HLA – Human Leukocyte Antigen (the name for MHC in humans)
We inherit three MHC class I genes from each parent and three MHC class II genes
- MHC class I and class II genes are all on the same chromosome; inherited together (known as a haplotype)
Each gene produces a protein, therefore we have six MHC class I molecules produced, and six MHC class II molecules produced
- Every molecule is expressed on the surface of a cell
- This is known as co-dominant gene expression
- No one allele is ‘stronger’ than another
MHC being able to present a huge array of peptides is important to individuals and the population as a whole
Therefore, having many different alleles that encode similar MHC molecules, but with different binding pockets, is advantageous
Gene mutations (point mutations) that change the MHC binding pocket are not selected against/may be selected for
This means over the course of evolution, new MHC alleles have been introduced

MHC is Polymorphic

Polymorphisms (changes in the amino acid sequence) are primarily found in the peptide-binding pocket of the MHC molecule.
There are 38,909 HLA alleles
There are (estimates vary):
- 8,098 HLA-A alleles
- 9,656 HLA-B alleles
- 8,084 HLA-C alleles
- 645ɑ and 2,486 β HLA-DP alleles
- 722ɑ and 42β HLA-DQ alleles
- 65ɑ and 4,581β HLA-DR alleles
This is known as polymorphism, and the MHC genes are the most polymorphic genes
The combination of MHC alleles you have on one chromosome is known as a haplotype

Genetics of MHC - Summary

MHC is polygenic
MHC is co-dominantly expressed
MHC is polymorphic (targeting the binding pocket)
Combined this protects us as individuals and as a species

MHC Restriction

T cells recognize the presence of pathogens indirectly
- The T cell receptor (TCR) recognizes peptides presented in MHC molecules
The TCR needs to recognize the MHC molecule as part of this pathogen recognition
The TCR is made in the thymus and is generated through a (somewhat) random process
The TCR needs to be assessed before it leaves the thymus to ensure it recognizes an MHC molecule

T Cell Receptor Development

T cell receptor (TCR) is made in the thymus randomly.
As T cells can only recognize and respond to pathogen peptides presented in MHC molecules, the newly developed receptor is examined to ensure that it can recognize ONE MHC molecule in that individual.
If there is no recognition, the developing T cell will die.
If the TCR recognizes an MHC class I molecule, then it will become a cytotoxic (CD8+) T cell.
If the TCR recognizes an MHC class II molecule, then it will become a helper (CD4+) T cell.

MHC Restriction Definition

MHC restriction refers to the fact that a randomly generated T cell receptor MUST recognize ONE MHC molecule made by that individual

HLA Matching for Stem Cell Transplantation

There are approximately:
- 8,098 HLA-A alleles
- 9,656 HLA-B alleles
- 8,084 HLA-C alleles
- 645ɑ and 2,486 β HLA-DP alleles
- 722ɑ and 42β HLA-DQ alleles
- 65ɑ and 4,581β HLA-DR alleles
Given the amazing amount of diversity in MHC (HLA) alleles it is difficult to find organ transplant donors and the chance of finding a match is:
- $\frac{1}{8000}$ for HLA-A
- $\frac{1}{9500}$ for HLA-B
- $\frac{1}{8000}$ for HLA-C

Clinical Relevance

Organ transplant rejection occurs primarily due to mismatches in HLA alleles
The T cells in the recipient recognize the peptide:MHC from the donor as foreign and treat the organ like they would an infection
The graft is attacked, and transplantation rejection occurs
(Transplantation drugs mostly target T cells to prevent their ability to attack the graft)
Diversity in MHC molecules is important for survival of both individuals and species, but is also clinically relevant in other respects
Susceptibility to (or protection from) certain autoimmune diseases
- Type I diabetes; HLA-DQ2 and DQ8 has an RR of 25, and HLA-DQ6 has an RR of 0.2
- MS; HLA-DR2 has an RR of 4.8
Susceptibility to (or protection from) a range of other diseases
- E.g. Narcolepsy
HLA allele matching between parents increases the risk of miscarriage
HLA (may) influence mate choice
- Through ‘olfactory attraction’
Lack of MHC genetic diversity in Tasmanian Devils has allowed a transmissible cancer to occur, which is having a devastating impact on Devil numbers

Here are the answers to the learning objectives in bullet points:

Describe the structure of MHC class I and class II molecules:
- MHC class I: Found on all nucleated cells; presents antigens to CD8+ T cells; has a transmembrane domain, an invariant domain, and a peptide-binding pocket.
- MHC class II: Found on antigen-presenting cells (APCs) like dendritic cells, macrophages, and B cells; presents antigens to CD4+ T cells; also has a transmembrane domain, an invariant domain, and a peptide-binding pocket.
Explain MHC class I and class II antigen processing pathways:
- MHC class I pathway: Processes antigens from the cytosol (e.g., viral proteins); involves the proteasome, TAP transporter, and the ER; peptides are loaded onto MHC class I molecules in the ER and transported to the cell surface.
- MHC class II pathway: Processes antigens from outside the cell (e.g., extracellular bacteria); involves endocytosis, lysosomal degradation, and fusion of vesicles containing MHC class II molecules with vesicles containing processed antigens; the peptide:MHC complex is then transported to the cell surface.
Compare and contrast MHC class I and class II processing, highlighting similarities and differences:
- Similarities: Both pathways involve the generation of peptide antigens, the binding of peptides to MHC molecules, and the presentation of peptide:MHC complexes on the cell surface.
- Differences: MHC class I processes antigens from the cytosol, while MHC class II processes antigens from outside the cell. They also differ in the cellular machinery involved and the types of T cells they present antigens to (CD8+ for MHC class I, CD4+ for MHC class II).
Define the genetic underpinnings of MHC:
- MHC genes are polygenic (multiple genes encode similar proteins), co-dominantly expressed (both alleles are expressed), and highly polymorphic (many different alleles exist for each gene, primarily affecting the peptide-binding pocket).
- In humans, MHC is called HLA (Human Leukocyte Antigen), and key genes include HLA-A, HLA-B, HLA-C for MHC class I, and HLA-DR, HLA-DQ, HLA-DP for MHC class II.
Understand MHC restriction:
- MHC restriction refers to the fact that a T cell receptor (TCR) must recognize both the peptide and the MHC molecule presenting it; T cells are selected in the thymus to ensure they recognize one of the individual's MHC molecules.
Appreciate the clinical importance of MHC:
- MHC plays a critical role in organ transplantation rejection, susceptibility to autoimmune diseases (e.g., type I diabetes, multiple sclerosis), and potentially mate choice; lack of MHC genetic diversity can lead to increased susceptibility to diseases (e.g., transmissible cancer in Tasmanian Devils).