Lecture 7 - Chapter 8

What is the MHC-peptide interaction that occurs in the MHC groove?

- Some amino acids anchor the peptide into the groove - Other amino acids are available to interact with a TCR

Basically we have this B cell, and it has these antibodies on the cell surface. It has about _____________ antibodies on the cell surface.

10,000

MHC class I and II loci have many more than ______ different alleles in mice and in humans.

100

T cell helper is able to bind that peptide in a complex with the MHC Class II. The CD__ molecule is what helps with that binding.

4

Class II pairs with CD___ and Class I pairs with the CD___.

4 8

Wherever with a cytotoxic T cell will recognize the antigen in complex with MHC Class I. This is the CD___ that helps that binding.

8

What is the structure of the class II MHC molecules? (2)

A 33 kDa α chain A 28 kDa β chain

What is the binding of the peptide in the MHC Class II molecules?

A peptide-binding cleft is formed by the pairing of the α1 and β1 domain that binds peptides of 13-18 amino acids in length.

The MHC classes have different gene products. Give an example of mice and human gene products.

A popular gene product in Mice MHC I is H-2K. In humans, a MHC I is HLA.

What does it mean that the MHC we exhibit are polymorphic (even though we know there are a fixed number of genes that we humans can encode?

Although an individual has a limited, fixed number of genes that encode these proteins, the whole species contains an enormous variety of combinations of these alleles. In fact, it's unlikely that any two individuals of an outbreeding species, like Homo sapiens, are identical for all the MHC proteins that cells express (except for monozygotic twins, triplets, etc.).

What difference does it make that MHC I are not heterodimers and MHC II are heterodimers?

Because MHC II are heterodimers, new molecules containing one maternal-derived and one paternal-derived chain are also produced.

Why is it that most transplantation don't work?

Because it is all based on the MHC. Unless we have the same MHC as the incoming organs then we will recognize that new incoming organ as foreign.

Why are transplantations so difficult?

Because of MHC polymorphism - we're all different from each other at the MHC, which is the basis for transplant rejection.

What does it mean that MHC alleles are codominantly expressed?

Both maternal and paternal MHC genes are expressed in offspring cells.

In MHC Class II molecules, how many subunits span the membrane?

Both.

MHC locus encodes three major classes of molecules - what are they?

Class I MHC genes Class II MHC genes Class III MHC genes

What's kinds of cells are MHC II found on?

Class II molecules are present on all antigen presenting cells.

Codominant Alleles

Each MHC gene product (i.e. each allele) is expressed on surface of individual cell.

So an H-2 parent b/b with and H'2 parents k/k will produce an offspring that is...

H-2 progeny b/k.

Wherever with a cytotoxic T cell will recognize the antigen in complex with MHC Class __.

I

T cell helper is able to bind that peptide in a complex with the MHC Class ___.

II

What is the purpose of inbreeding mice when studying Class I/II molecules?

Inbreeding of mice has allowed for more standardized MHC genotypes to control variability (i.e. they will all have the same haplotype).

How did Class I/II molecules exhibit diversity at the individual level?

Individuals express MHC alleles inherited from both parents so unlike the allelic exclusion in the B cell, both alleles are expressed for MHC and that gives us more diversity.

For MHC class I - each allele protein spans the membrane. Where does the second subunit come from?

It doesn't matter because the plasma membrane is only spanned by the one gene product.

EXAM QUESTION: WHAT DOES POLYMORPHISM MEAN IN REFERENCE TO MHC PROTEINS AND WHY IS IT IMPORTANT?

It means that we are polymorphic as a species. As a species, we can recognize all of the different invaders such that someone survives (important from a evolutionary perspective).

What is the structure of the MHC Class I molecules? (2)

Larger 45 kDa glycoprotein α chain that spans the plasma membrane in the host cell Smaller 12 kDa β2-microglobulin protein

if we think about all the different genes that we have, we all have the same genes essentially. 99% of us have the same genes but the exception is ______.

MHC

WHICH MHC CLASS? Present peptides to CD8+ T cells - REALLY IMPORTANT.

MHC I

What's kinds of cells are MHC I found on?

MHC I are on every cell that has a nucleus.

WHICH MHC CLASS? Present peptides to CD4+ T cells - REALLY IMPORTANT.

MHC II

Does MHC I or MHC II have more diversity and why?

MHC II because they not only express either the mom or dad MHC II allele but the mom and dad MHC II alleles can be mixed in forming the heterodimer MHC II protein.

How does this limited group of molecules present the vast diverse array of possible antigen peptide fragments?

MHC is promiscuous: a given MHC molecule can bind numerous different peptides, and some peptides can bind to several different MHC molecules. I is not just binding one antigen like an antibody would - it can bind many (BUT ONLY ONE AT A TIME). So it is not specific like the antibody binding!

________ ______________ vary much more from individual to individual than any other known protein.

MHC proteins

Transplantations fail because we are all different at the ________.

MHCs

What does it mean that most genes are monomorphic?

More than 99% of the individuals in a species are genetically identical at that site.

Each MHC has _____ peptide binding site.

ONE

So we know that MHC can bind lots of different peptides - how many bind at a time?

Only one at a time.

_______ are specific to B cells

RAG

What are the two classes of MHC and which T cells are they associated with?

Th recognize in context of MHC class II Tc recognize in context of MHC class I

What does it mean that the MHC cells are codominant?

That means each cell expresses both the maternal and paternal alleles of these genes.

MHC proteins form a complex with fragments of antigens (usually protein). How is an immune response initiated from this?

The T cell receptor recognizes and binds to the MHC- antigen complex - this then goes forward to initiate the immune response.

Will the parents (b or k) accept transplants from their offspring (b/k)?

The parents will reject transplants from the offspring, because they contain "foreign = nonself" MHC proteins.

What are the plasma cells that surround the B cells?

The plasma cell is really an antibody factory (just produces copious amounts of antibodies). The plasma cells are secreting the antibodies identical to the B cell (they all have the same antigen binding sites). But the plasma cell can produce an IgE as opposed to an IgG or IgA. They will always have the same antigen binding portion but they can secrete all different isotypes.

Knowing that the MHC alleles are codominant - will the progeny accept transplants from either of it's parents strains?

The progeny (b/k) of these crosses will accept transplants from either parent strain- either b or k haplotypes; they recognize both as "self".

What is the binding of the peptide in the MHC Class I molecules?

The α1 and α2 domains form a cleft region that binds a 8-10 amino acid-long peptide fragment from an antigen.

In MHC Class I molecules, how many subunits span the membrane?

There is only one domain that goes through the membrane.

What is the conformation of MHC II molecules?

They are heterodimers.

What is the function of Class III MHC genes? (2)

They are involved in making and encoding for complement and inflammation proteins.

How are MHC molecules expressed (i.e. where are they expressed)?

They are on the surface of antigen-presenting cells.

If the progeny b/k gives a skin graft to just b or k, what is the response and why?

They will reject it because they see the other haplotype that is there as foreign.

What is the advantage of having a lot of diversity in the Class I/II molecules?

This diversity provides flexibility in responding to unexpected environmental changes (i.e. pathogens), now and in the future.

What is the advantage of expressing our MHC proteins codominantly?

This gives the best chance for an organism to have SOME capability of presenting all the possible antigen peptides it encounters.

The plasma cell can secrete any isotype that it needs to - how does it decide what isotope to produce?

This is based on the environment that it is exposed to.

What is the strategy when doing transplantations?

This is the idea with transplantation - they are looking for a good match. You need to find someone who is close to you so that you can manage the immune response.

What is a disadvantage of expressing our MHC protein codominantly?

This makes transplantation somewhat difficult since nonmatching MHC patterns will result in rejection of transplanted tissues.

For MHC I, the allele encoded by mom and dad will produce how many MHC I proteins?

Two - one from each parents allele.

We all have our own set of the MHC molecules - how does this affect how we respond to viruses?

We will all respond differently to whether the MHC will bind or not.

Describe the biochemistry of the binding that occurs in the MHC groove.

You can have some amino acids that anchor (8-12 amino acids) in the MHC groove. The MHC molecule has a groove where the peptide can bind. But sometimes you'll have amino acids popping out and they will interact with the T cell.

How is it determined which MHC genes are being expressed (i.e. we already know MHC I and II are on being expressed but which genes specifically)?

You will always show all your possibilities if the MHC's are being expressed on the surface.

If we stuck the skin on a recipient of the same mouse, then it will be ________________.

accepted

Alleles can also differ between individuals (i.e. there is enormous diversity it the number of different ___________________ of the Class I/II molecules).

allotypes

If b was mated with b, inbred situation, you'll get a haplotype that is ___.

b

So on a nucleated antigen presenting cells you will show...

both MHC I and MHC II.

Alleles for MHC genes are ___________________.

co-dominant

Both sets of genes are expressed; that is, the MHC genes are ___________________.

co-dominant

MHC alleles are __________________ expressed.

codominantly

With MHC II we have more _______________ if you look at the two different subunits, you need both to create the binding site for the antigen.

combinations

They're progeny have these potential combinations. Both are expressed in the offspring cells, giving the offspring further ____________ if mom and dad come from different genetics.

diversity * This gives the offspring the best chance to have different antigen combinations.

High resolution gene mapping and DNA sequencing indicates that the MHC regions of both mice and humans contain __________ of genes.

dozens

MHC I binds peptides derived from...

endogenous intracellular proteins.

MHC II binds peptides derived from...

exogenous extracellular processed antigens.

MHC polymorphism is determined in ______________.

germ-line

Letters and numbers identify various MHC alleles. The combination of possible alleles that an inbred strain has is said to be its ________________.

haplotype * So at different loci, we have different haplotypes (e.g.at the H-2 loci, an inbreb strain would have a b/b/b/b/b haplotype.

Allelic forms of MHC genes are inherited in linked groups called ________________.

haplotypes

Different inbred mouse strains have different _________________.

haplotypes

. In the case of inbred strains, the genes on both chromosomes are genetically __________________, because each animal inherits the same genetic information from each parent.

identical

T cells respond to antigen only if...

if the antigen is "presented" to them by antigen-presenting cells (APCs).

If mom and dad are genetically different, you will have more diversity in the MHC leading back to the idea that being inbred will have more __________________ __________________.

immunological deficiencies

If mom and dad are different haplotypes then you will get both b and k so your diversity has _________________.

increased

Class I/II molecules exhibit diversity at _____________ AND __________ levels.

individual species

The only way the T cell will be activated is...

is if it can bind the MHC and determines whether you will respond effectively to an invading pathogen.

TCR recognize a short peptide carried in the groove of a _________ _____________ _________________ protein on the surface of an antigen-presenting cell (APC).

major histocompatibility complex (MHC)

Each MHC can bind ___________ peptides (interaction of a protein with its "substrate" is relatively __________________).

many (they are all different) nonspecific

Most genetic loci known are _________________.

monomorphic

If you only have one type of MHC then you are limited to which antigens can bind the MHC. More diverse MHC you can respond to many ________ (more/less) different antigens.

more

The beta-microglobulin of MHC I is encoded by a __________________ gene on a separate chromosome and can be derived from either parent.

nonpolymeric

Each individual inherits ____ haplotype from each parent.

one

One B cell expresses how many Ig?

one

When two different strains are mated, then the offspring carry _______ copy of each parental haplotype.

one

No one in the room has the same MHC genes because it is ____________________.

polymorphic

Class I and II molecules exhibit _______________ in the peptide-binding region.

polymorphism

MHC class I and II loci - although an individual has a limited number of the genes, the whole species (the whole human population) has a huge variety of the combination of these alleles. This is important because as a species, one probably will survive from a virus because we have such diverse ___________________ at our alleles.

polymorphism

If you put b graft on a mouse with no b haplotype, the skin graft will be __________________.

rejected

If we are trying to put on a skin graft from one mouse to another, when anything foreign goes into the body, we will attack it - this is called graft skin _______________.

rejection

MHC polymorphism is really what determined disease ________________ or ____________________.

resistance susceptibility

Molecules that serve as carriers of antigenic material on the surface of APCs, are called...

the major histocompatibility complex (MHC) proteins.

MHC is really important - it has to do with this _____________ ______________________ (i.e. with reference to transplantations).

tissue compatibility

What does histocompatibility mean?

tissue compatibility

In the case of Class II, there are the ____ subunits spanning the molecule.

two

Know the T cell receptor will only engage an antigen when...

when it is bound to a MHC on the surface of an antigen presenting cell.