622 11/3 GLA MHC and Antigen Presentation

Antigen Presenting Cells

part of adaptive immunity, break down pathogens into little pieces called antigens and then present them to T cells so they know what the enemy looks like

T Cells

in adaptive immune system, has specific receptors to recognize small specific antigens

B Cell Receptors/Antibodies vs T Cell Responses

b cell receptors/antibodies can bind and respond to unprocessed, native antigens

t cell responses require antigen processing and presentation

Antigen Processing

the breakdown of the protein components of a pathogen into tiny pieces (protein fragments) called antigenic epitopes

Antigen Presentation

the ability of antigen presenting cells (APCs) to display, or present the small pieces of pathogen made by antigen processing on its surface as a signal to T cells that a foreign antigen is present

3 Professional APCs

dendritic cells

b cells

macrophages

Dendritic Cells

the best APCs, mostly reside where tissues are in contact with external environment (skin, GI, respiratory)

named so bc of their dendrite like projections

CD

cluster of differentiation

CD Markers

surface markers of cells, some of them have functions while others simply serve as identifying marker on that cell

CD Markers Table

Epitope

a small peptide of a foreign antigen

What is the function of the MHC in APCs?

in APCs, an epitope is loaded into MHC proteins which are then lifted to the surface, like a red flag, telling T cells that there is an infection present

MHC (Major Histocompatability Complex)

complex of cell surface proteins that help the adaptive immune system, specifically T cells, recognize self vs non self

Human Leukocyte Antigen Genes (HLA)

genes in humans that express MHCs

estimated to be more than 10,000 alleles in the human population

What determines MHC protein affinity for potential antigens?

its shape/conformation

this is important bc MHC genes have lots of variability, and having such variations results in a diversity of antigens that can be loaded onto the MHC proteins

2 MHC Classes

class i

class ii

MHC Class I

expressed by all nucleated cells and platelets in the body (not rbcs)

presents antigen to CD8+ cytotoxic T cells

MHC Class II

only produced on professional APCs

presents antigen to CD4+ helper T cells

Shape of MHC Class I

binding cleft and main structure made up of one chain (alphe chain)

a structural component called b2-microglobulin which holds the MHC

Shape of MHC Class II

two main chains (a and b) which together make up the binding cleft

What length of peptides to MHC Class I bind to, and how?

they bind to peptides 8-10 AA in length

binding cleft is closed at the ends, making MHC like a baseball glove with the peptide as the baseball

Anchor Residues

specific amino acids essential for binding peptide to a particular MHC Class I molecule

Why are APC so important?

APCs display both MHC class i and ii receptors, so they are able to present antigen to both cytotoxic and helper T cells

all other nucleated cells in the body display only the MHC i receptor and therefore are only able to present antigen to cytotoxic T cells

What length of peptides to MHC Class II bind to, and how?

they bind to peptides 10-30 AA in length

cleft is open at both ends, like a hot dog that is too long for the bun so the peptide sticks out at both ends

What is unique about the peptides that bind to MHC Class II?

they have internal conserved motifs, and lack anchor residues at the ends

2 Pathways Antigens can be Processed and Presented

MHC class i pathway

MHC class ii pathway

What types of pathogens are processed using the MHC Class I Pathway?

intracellular/endogenous pathogens (like viruses)

What types of pathogens are processed using the MHC Class II Pathway?

extracellular/exogenous pathogens (like most bacteria)

Common Features of the MHC I and MHC II Pathways

breaking down the antigen into small pieces and then association with an MHC protein complex and transport to the cell surface

How does our immune system respond to intracellular infections?

by having cytotoxic CD8+ cells recognize these infected cells and destroying them

process is mediated by the MHC class I pathway

MHC Class I Pathway Diagram

6 Steps in MHC Class I Pathway

Antigens in the cytoplasm are ubiquitinated and targeted for degradation by the proteasome

Proteosomes chop up the proteins into small peptides (8-10 amino acids in length)

Transporter associated with antigen presentation (TAP) uses ATP fuel to transport peptides into the lumen of the endoplasmic reticulum

Tapasin brings empty MHC Class I molecules into close proximity to TAP and the antigenic peptides

The peptide is fit into the binding cleft of the MHC Class I molecule (like a baseball glove) and Beta2-microglobulin holds the MHC in the correct shape

The MHC I/peptide complex is now stable and transported to the surface for display to CD8+ cytotoxic T cells

Steps 1-2 MHC Class I Pathway

antigens in cytoplasm are ubiquinated and targeted for degradation by the proteasome

proteasomes chop up the proteins into small peptides (8-10 aa in length)

Steps 3-4 MHC Class I Pathway

transporter associated with antigen presentation (TAP) uses ATP to fuel transport peptides into the lumen of the ER

tapasin brings empty MHC class i molecules into close proximity to TAP and the antigenic peptides

Steps 5-6 MHC Class I Pathway

the peptide is fit into the binding cleft of the MHC class i molecule like a baseball glove, and b2-microglobulin hold the MHC in the correct shape

the MHC i/peptide complex is now stable and transported to the surface for display to the CD8+ cytotoxic T cells

b2-microglobulin

part of MHC class i structure, holds MHC in the correct shape

associated with MHC i in the rough ER

How can our immune system attack cancer?

using the MHC class i pathway, endogenous cancer antigens are presented on the cell surface so the cells can be destroyed by the cytotoxic T cells

What cells perform the MHC Class II Pathway?

only professional APCs (dendritic cells, B cells, macrophages) because they are the only cells that express MHC II on their cell surface

MHC Class II Pathway Diagram

7 Steps of MHC Class II Pathway

Extracellular antigens or whole microbes are taken up by APCs and packaged into endosomes (like the phagolysosome after phagocytosis or the endolysosome after endocytosis)

Intracellular killing mechanisms cause the endosomal pH to drop. The acidified compartment triggers activity by enzymes called proteases (for example, lysozyme), that chop up the antigens within the endolysosomes

Empty MHC Class II molecules are constantly being synthesized in the ER. At this point, the empty binding cleft is held open by a peptide called the invariant chain

Vesicles containing these empty MHC Class II molecules fuse with the acidified endolysosomes

The activated enzymes in the end-some then chop up the invariant chain and leave only a piece of it in the binding cleft called CLIP (Class II invariant peptide)

A protein called HLA-DM replaces CLIP with the antigenic peptide

The MHC Class II/peptide complex is now stable and is transported to the surface for display to helper CD4+ T cells

Steps 1-2 MHC Class II Pathway

extracellular antigens or whole microbes are taken up by APCs and packaged into endosomes (such as the phaoglysosomes after phagocytosis or the endolyososome after endocytosis)

intracellular killing mechanisms cause the endosomal pH to drop, and acidification triggers activity of proteases that chop up the antigens within the endolysosomes

Steps 3-4 MHC Class II Pathway

empty MHC class ii molecules are constantly being synthesized in the ER, and the empty binding cleft is held open by a peptide called the invariant chain

vesicles containing the empty MHC class ii molecules fuse with the acidified endolyzozomes

Steps 5-7 MHC Class II Pathway

the activated enzymes in the end-some chop up the invariant chain and leave only a piece of it in the binding cleft called the CLIP

a protein called HLA-DM replaces CLIP with the antigenic peptide

the MHC class ii/peptide complex is now stable and is transported to the surface for display to helper CD4+ T cells

CLIP

class ii invariant peptide, the piece of the invariant chain left in the MHC class ii peptide after it has been chopped by the activated enzymes in the end-some

Where is the antigen loaded onto MHC II?

the endolysosome

What receptors do professional APCs have on their surface?

MHC type i and MHC type ii

If professional APCs have MHC I and MHC II receptors, what does helper T cell (MHC II) presentation accomplish?

cytokine secretion to activate a general immune response, which eventually rids the body of the antigens

4 Ways APCs are Involved with Different Types of T Cells

activation of naive T cells (whether CD4 or CD8) is done by dendritic cells, making these cells the key to early T-cell differentiation

stimulation of CD8⁺ effector cytotoxic T cells, causing them to kill infected cells, is done using the MHC class I pathway

activation of CD4⁺ effector T cells is done mostly by dendritic cells, with assistance from the other professional APCs (B cells and macrophages). These are the only cells that contain the MHC class II protein needed for this process

activation of memory T cells is mostly done by B cells and macrophages

Dendritic Cells (APC) Importance to T Cells

activation of naive T cells (whether CD4 or CD8) is done by dendritic cells, making these cells the key to early t-cell differentiation

APCs Impact on CD8+ Effector Cytotoxic T Cells

stimulation of CD8+ effector cytotoxic T cells by APCs causes them to kill infected cells is done using the MHC class i pathway

APCs Impact on CD4+ Effector Cytotoxic T Cells

activation of CD4+ effector T cells is done mostly by dendritic cells, with assistance from other processional APCs

these are the only cells that contain the MHC class ii protein needed for this process

Impact of APCs on Memory T Cells

activation of memory T cells is mostly done by B cells and macrophages

Cross-Presentation

ability of dendritic cells to load exogenous pathogens onto MHC i proteins for presentation of cytotoxic T cells, leading to destruction of the infected cell

this differs from the way exogenous pathogens are usually loaded via the MHC ii pathway

Cross-Presentation Diagram

Classes of MHC Genes

class i

class ii

class iii

Variability of MHC Genes

have the greatest diversity of alleles found in different individuals inside a population (aka high polymorphism), with over 10,000 unique alleles in the population

the most genetically diverse locus present in any mammalian genome

How many MHC genes do we have and how do we get them?

each person has 12 total MHC class i and ii genes

each parent donates 6

Co-dominance of MHC Genes

they are all expressed equally (not a blend)

3 Human Class I HLA Genes

HLA-A

HLA-B

HLA-C

3 Human Class II HLA Genes

HLA-DP

HLA-DQ

HLA-DR

MHC Haplotype

made up of the set of MHC alleles on each chromosome

because each individual has two copies of each chromosome, everyone has two HLA haplotypes

each parent donates one haplotype

MHC Haplotypes Diagram

HLA-DR3 Allele

assocaited with an increased risk for certain autoimmune conditions including, type i diabetes, systemic lupus erythematesus, graves disease and myasthenia gravis

Autoimmunity

when your immune system attacks your own body

Why do some MHC alleles have a higher association with an autoimmunity?

for a peptide to be presented to a T cell it has to perfectly fit into the binding cleft of the MHC

often in autoimmunities, a self-peptide fits just perfectly into a patient’s MHC and is presented to T cells, starting an inappropriate immune response

Psoriasis as Example of Relationship Between MHC and Autoimmunity

Chart of Diseases Associated with HLA Alleles

Advantage vs Disadvantage of Certain MHC Alleles

some alleles can present a peptide with high affinity to responding T cells, activating more of them, and enabling a better immune response to infection

some alleles can make a person more susceptible to disease if the allele cannot bind to or present peptides to T cells, limiting the immune response and making infection more severe (ex: COVID)

How does MHC variation help protect from disease?

since the immune system of each individual is different, perfect pathogens cannot evolve to spread through a population

possibly less likely for microbe to imitate MHC alleles if there is a large variety of MHC

MHC and Transplant Matching

the differences between MHC molecules of the donor and recipient are the major cause of tissue incompatability and transplant rejection, highlighting the importance of tissue typing before transplantation

name stems from its initial recognition as the site of genes that cause T cells to reject tissues transplanted from unrelated donors to recipients

Which MHC Classes have a direct role in antigen presentation?

class i to CD8

class ii to CD4

Where are the MHC genes located?

the short arm of chromosome 6

the do not participate in genetic recombination