MHC and Specific Receptors Flashcards
Explain the concept of MHC restriction
Peptide binds to an MHC that can be recognized by a TCR
If you have the same peptide bind to a different MHC, the same TCR will NOT recognize it
If you put a different peptide in the same MHC but use a different TCR, it won’t be recognized either
Describe the structure of an MHCI molecule
The MHC I molecules are made up of 3 alpha chains and beta 2 microglobulin (the third alpha chain is membrane proximal)
What part of the MHC I molecule has variability?
Note that the variable regions of the TCR are in alpha chains 1 and 2 and NOT alpha 3
They’re also only in certain places in alpha 1 and 2
On what part of the MHCI molecule is peptide antigen recognized?
The variable regions of the MHC I molecule (also note that this is the same thing as HLA class I) are the ones that recognize peptide antigen
CD8 on the surface of the CD8+ T cell binds to ___ domain/chain of the MHCI molecule on the target cell
CD8 (on the surface of the CD8+ T cell) binds to alpha 3 domain of the MHCI molecule on the target cell)
So the CD8 molecule binds to the a3 domain to stabilize the interaction between the T cell receptor and the rest of the MHC molecule
For MHC I to be stably present on the cell surface, what 3 molecules need to be present?
Alpha chain
B2 microglobulin
Peptide
In general, MHC I binds (small/large) peptides
The MHC has charged regions which can attract and repel certain peptides
Note the peptide size: in general, MHC I binds *small peptides
The side chains of the peptide and the MHC molecule are joined together by ___ bonds, which are very stable
At the C and N terminus, there are H bonds (not covalent) being made between the peptide side chains (in yellow) to the MHC molecule (the white blob of beta sheets)
*note that the H bonds here are very stable*
T/F: Two different kinds of peptides would have to bind different kinds of MHC molecules, even if the peptides are structurally similar
Falsehood. Two different kinds of peptides can bind the same MHC (due to their structural similarity)
What is the significance of an anchor residue in MHCI-peptide binding?
Anchor residues – residues that can go further down into the MHCI and facilitate hydrogen bonding there (so they’re effectively acting as anchors)
How are peptides of various lengths able to fit into the MHCI?
The point: some AA’s, depending on their size, can fit into a bulge in a peptide such that the peptide can still fit into the MHC molecule (those particular AA’s may or may not be recognized but the point is that there are various conformations that a peptide can take to be able to fit into the MHC)
**recall that the peptides here are generally small, like max of 9 aa’s**
What’s the point here?
The point: regardless of whether the peptide goes all the way deep into the MHC molecule or it stays mostly superficial, much of the peptide is interacting with the alpha helices of the MHC I
There are 3 genes in the HLA locus (aka the MHC locus), namely, ___
There are 3 genes in the HLA locus (aka the MHC locus)
HLA A
HLA B
HLA C
Describe the process of peptide processing for MHCI
When you have viral protein or protein from a bug, the protein gets unfolded and Ub tagged in the cytosol for break down in the proteasome
The proteasome breaks the protein down to its peptide components and those peptides are sent to the ER (they enter via TAP, transporter ass’d w/ antigen processing)
In the ER, the MHC molecule is being synthesized. Prior to the synthesis of the Beta 2 microglobulin chain, the premature MHC molecule is bound to Calnexin (think its the protein leading to the next step, which is being kicked off by B2 microglobulin once its synthesized)
The mature MHC binds the antigen peptide after its been chopped off at the N terminus by an ER amino peptidase in the ER and makes its way to the Golgi, where it’ll packaged in a vesicle and be sent to the cell surface
At the surface, the MHCI and peptide complex is such that the peptide is exposed to the outside, where it’ll be met by the TCR and CD8 molecules on the surface of the CD8+ T cell
**proteins that make up the loading complex: Calreticulin, tapasin, Tap proteins and ERp57)
Recall that the proteasome consists of alpha and beta subunits as well as a regulatory cap. What is the proteolytic part of the proteasome?
What is the significance of the following subunits: Lmp2, Lmp7, MecL1?
What happens when PA28 replaces the 19S cap?
Recall that proteasomes have alpha and beta subunits, the proteolytic subunits being the beta subunits
Lmp2, Lmp7 and MecL1 alter digestion pattern to facilitate class I friendly peptides
PA28 replaces 19S cap; “speeds up” peptide production!
Describe the structure of the MHCII molecule
MHC II has 2 alpha subunits that make up the alpha chain, and 2beta subunits that make up the beta chain
T/F: MHCII binding peptides are about the same size as those that bind MHCI
Falsehood. MHCII peptides are usually longer (something-teen long)
The variability in the MHC II molecule is in which subunit?
**Notice that variability in the MHC II molecule is in the Beta chain, specifically, the Beta 1 subunit**
CD4 on the surface of CD4+ T cells binds to which subunit of the MHCII molecule?
Note that the CD4 molecule on the CD4+ cell interacts with the B2 subunit of the MHCII molecule (again, acting to stabilize that interaction between the TCR, the rest of the MHCII and the peptide antigen in between)
Describe the process of peptide processing for MHCII
**note that here the antigen proteins are extracellular ones, taken up by endocytic vesicles in the APC**
In the endosome, the antigen protein is chopped up and the peptides hang out while in the ER, MHCII is being synthesized
In the ER, newly synthesized MHCII is bound by the Invariant chain, which sits in the newly synthesized MHCII before it goes out of the Golgi to the endosome to get the antigen, and its also the signal for the MHCII to leave the ER and go to the Golgi.
The MHCII with the invariant chain in it make their way to the Golgi, where they’re packaged off to meet the endosome containing the antigen peptides. Inside the vesicle with the MHCII are HLA-DM and DO, which will either open the MHCII for peptide loading, or close it.
Once we reach the endosome, note that the invariant chain is chopped off and a part of the chain called CLIP protein stays there and sits in the MHCII binding pocket until there’s enough HLA-DM around to get rid of it, open up the MHC molecule, and load peptide antigen
**note that a signal that would increase HLA-DM is something like a pro-inflammatory cytokine or something**
After being loaded with peptide antigen, the MHCII goes to the surface of the cell where it’ll have the peptide exposed with the TCR on the CD4+ T cell and CD4 molecule ready to interact with the MHCII and the peptide
Describe the role of a superantigen
Superantigens can bind the TCR and MHC and bring them together, independent of a specific antigen (meaning that the TCR and MHC will just recognize whatever that superantigen with no particular specificity, leading to activation of downstream inflammation/cytokine release, so I’m guessing this is on of the ways you get a cytokine storm
e.g. Staph or some viruses
**called super because the downstream response is massive**
How would you determine how many TCRs are on a cell’s surface?
Here you’re trying to see if an MHC-peptide complex can bind the TCRs so you basically tag the complex with a fluorophore and if there’s binding, you can visualize it
If you want to know how many TCRs are on the cell surface, you just add more of the Antigen-MHC complexes, you have the “avidity effect” and basically you have more TCRs binding >> increased fluorescence and you can quantify that
T/F: all the genes for both MHCI and II are on the Class II region
Falsehood. On the HLA locus, you have the Class II region that includes all the MHC II genes. There’s also the Class I region that has all of the Class I genes. Note that on the Class II region, there are also genes involved in MHCI, like those for TAP. The point here is that evolutionarily, so as not to lose them, the genes were clustered together on that region
*There are also non classical MHCI genes: HLA E and HLA G*
HLA-E binds nonamer peptides similar to signal sequences.
HLA-G present on fetal placental cells for immune tolerance in pregnancy
What exaxctly is ankylosing spondylitis?
AS is essentially fusion of the vertebrae which results in pain and what not
