MHC Notes
The Major Histocompatibility Complex (MHC) - Antigen Processing and Presentation
Learning Outcomes
By the end of this session, students should be able to:
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:
Peptide:MHC
Co-stimulation
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:
for HLA-A
for HLA-B
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).