MDSC 321: Major Histocompatibility Complex (MHC)

Major Histocompatibility Complex

Cells surface glycoproteins that bind antigens and "display" them on the host cell surface for recognition by T cells.

What was MHC first recognized for?

Its role in self/nonself discrimination and transplant rejection.

When transplanted, tissue is recognized as

Foreign by the recipient's immune system (T cells).

MHC proteins are critical for?

The display of Ag to T cells, T cells can only see Ag in context of self MHC.

Expression of MHC by an individual can define?

The individual's susceptibility to disease as well as the tendency for the development of autoimmunity and allergies.

Function of MHC Class I

Presentation of cytosolic antigens to cytotoxic T cells.

Function of MHC Class II

Presentation of extracellular/vesicular antigens to helper T cells.

Function of MHC Class III

Secreted proteins; not involved in antigen presentation to T cells. Includes complement, innate immune cytokines.

MHC genes are polygenic meaning -

3 from mum, 3 from dad = all expressed, 6 different MHC expressed on surface.

The MHC gene complex is organized along which chromosome in humans?

Chromosome 6 (Human Leukocyte Antigen; HLA)

The MHC gene complex is organized along which chromosome in mice?

Chromosome 17 (H-2)

Class I MHCs present what to activate what?

Altered self Ags or internal pathogens (ex: viruses) to activate appropriate cytotoxic T cells.

Where are class I MHC gene products found?

On nearly all nucleated cells of the body (except red blood cells)

MHC I genes are encoded in which regions in humans?

HLA-A, HLA-B and HLA-C.

What does each gene encode?

A single a chain proteins (which pairs with B2-microglobulin).

What do class II MHCs do?

Present processed exogenous Ags (ex: extracellular bacteria) to helper T cell.

Where are Class II MHC gene products expressed?

Only on membranes of Antigen Presenting Cells (APCs including macrophage, dendritic cells and B-cells).

What regions are Class II MHC genes located in in humans?

HLA-DP, HLA-DQ and HLA-DR, each regions encodes both an a and a B chain.

T cells - MHC class I and II expression

Lots, little

B cells - MHC class I and II expression

Lots, lots

Macrophages - MHC class I and II expression

Lots, a bit less but still lots

Dendritic Cells - MHC class I and II expression

Lots, lots

Epithelial cells of thymus - MHC class I and II expression

Little, lots

Neutrophils - MHC class I and II expression

Lots, none

Red blood cells - MHC class I and II expression

None, none

Diversity in the MHC locus is ________ within a given species (5-10%) than typically found in a gene between species.

Greater

Within a population, is there lots of MHC diversity?

Yes

Although there is a great diversity in MHC between individuals in the population -

All MHC molecule in an individual are the same.

What causes MHC diversity?

Not from gene rearrangement but from polymorphism (multiple alleles) within the MHC gene loci.

What needs to be true for an allele?

Must be present in more than 1% of the population, otherwise the variant is just known as a mutation.

How many alleles are there for each MHC gene?

From 3 to 1500 (MHC I HLA-B gene).

How does MHC inheritance work from mum and dad?

3 MHC I and 3 MHC II from mum, 3 MHC 1 and 3 MHC II from dad = 12 total MHCs.

Which MHCs are expressed on all nucleated cells (co-dominant)?

All 6 MHC I

How many MHC molecules are expressed on APCs?

6 MHC I + 6 MHC II = 12 MHCs

Diversity within MHC genes is where?

In the peptide-binding cleft.

What analogy do we use to describe peptide binding for MHC I?

Birds nest

What analogy do we use to describe peptide binding for MHC II?

Hot dog bun

Describe the Class I cleft?

Closed at its ends and can only hold a peptide of 8-10 amino acids. Hold ends down with a central bulge to interact with TCR.

Anchor residues

Hold peptide in place (often hydrophobic).

Each MHC can bind a diverse array of what>

Peptides

The different peptides have a number of _________ in common with similar ______ properties?

Anchor residues, AA

Describe Class II MHC peptide binding?

Class II is open at its ends, can hold a peptide of 13-18AA. Peptide is exposed flat across surface. Anchor points distributed across ends and center of peptide. Interaction involve hydrophobic residues.

What happens because the peptide binding cleft of MHC II is open at each end?

Peptides of varying lengths can easily be accommodated provided the required anchor residues are present.

What can T cells recognize?

Peptides derived from foreign Ag presented within the binding cleft of MHC.

What does Ag processing involve?

Degradation of Ag into peptides.

What does Ag presentation describe?

The binding of the peptide by MHC and displaying the peptide at the cells surface to interact with T cells.

Class I MHC molecules bind peptides derived from?

Endogenous Ags processed in the cytoplasm.

Class II MHC molecules bind peptides of?

Exogenous Ags processed in the endocytic pathway.

What is the purpose of Ag processing?

To generate peptides that will fit in the MHC binding cleft.

How long are MHC I peptides?

8-10 AA long

How long are MHC II peptides?

13-18 AA long

What does antigen processing also need to do?

Translocate the peptides from their source (cytoplasm, extracellular environment) to the newly formed MHC molecules.

What are the steps of loading MHC I?

1. Identification and cleavage of target proteins

2. Transport to endoplasmic reticulum

3. Loading onto MHC I

4. Expression on cell surface

How are proteins degraded for MHC I antigen processing?

They are degraded by proteasomes.

Proteasomes

Large cylindrical particles containing 4 rings of protein subunits with 10-50 Å central channel that act to chew up protein.

Where are peptides transported after being degraded by the proteasome?

From the cytoplasm to the ER by the Transporter of Antigenic Peptides (TAP), a heterodimer of the TAP1 and TAP2 proteins.

Once in the ER, peptides are loaded onto what?

Pre-formed MHC I that are stabilized by chaperone proteins.

What happens once a peptide is loaded onto the MHC I?

MHC I is released from the chaperone.

Where do loaded MHC I traffic?

In vesicles to the cell surface.

What are the steps of MHC II loading?

1. Internalization of target molecules

2. Digestion of targets

3. Synthesis of MHC II

4. Co-localization of MHC and antigen compartments

5. Peptide loading on MHC II

6. Transport to cell surface

What is antigen internalization?

Extracellular proteins are internalized through either phagocytosis or endocytosis. Internalized peptides are contained in phagososmes or endosomes.

What type of cells do phagocytosis?

Macrophages

What type of cells do receptor mediated endocytosis?

B cells

Peptide generation

Ag is degraded within the endocytic pathway to 13 to 18 AA in size. This is a flexible number.

Endocytic pathway

Early endosomes (pH 6-6.5) to late endosomes or endolysosomes (pH 5-6) to lysosomes (pH of 4.5-5)

Synthesis of MHC II in ER

Stabilization with chaperone proteins to block inappropriate self peptides from binding.

Co-localization of MHC and antigen compartments

Vesicles containing newly-synthesized MHC II traffic from ER through the Golgi, and eventually fuse with endolysosomes.

Peptide loading onto MHC II

Chaperone proteins degraded, replaced by peptide fragments.

Surface expression

Once loaded with an appropriate peptide, the complete MHC II-peptide complex traffics to the cell surface. Fusion of vesicle with the cytoplasmic membrane leads to expression of loaded MHC II on the cell surface.