The Meaning Of Self: HLA System And Antigen Presentation Flashcards
Studies of what led to the discovery of the MHC?
transplant rejection
How are MHC antigens (HLA) presented on the cell surface?
As glycoproteins
What is the name of the human MHC and why?
HLA (Human leukocyte antigen) because it was discovered by studying the antigens concentrated in blood
What is the main function of HLA1 and HLA2 antigens?
They bind exogenous and endogenous peptides derived from self and non-self proteins to allert the immune system about infection and pathogen presence
What are the two monomers that make up the HLA-I heterodimer?
a1,a2,a3 heavy chain and one B2microglobulin light chain
Which domains form the peptide-binding cleft for the HLA-1?
a1 and a2
What are the domains of the class 2 glycoproteins?
a1,a2 chain and b1,b2 chain
What domains form the protein binding cleft of HLA-2?
a1 and b1
What are the paired, membrane-proximal domains of HLA-1 and HLA-2 homologous to?
How are the distal domains arranged?
Proximal domains are like Ig domains
Distal domains are folded into sheets criss-crossed by two helices
Where do antigens bind to the HLA structure?
between the 2 distal helices in the variable region
What determines the shape of the antigen binding site of the HLA molecule?
the amino acid sequence of the HLA component
How are the antigen binding grooves different for HLA1 and HLA2?
HLA-II groove is open at both ends so it can accommodate a longer protein (12-30AA residues)
HLA-1 groove has constricted ends so it can only bind residues from 8-10AA in length
Unlike many hormone receptors, HLA can bind ________________ different peptides as long as they are __________________________.
many; structurally related
Do the residues that anchor peptides into the MHC domain need to be identical?
No, but they need to have enough structural similarity to “fit” the MHC pockets.
Why are the anchor positions not easily identified for class 2 HLA molecules?
The length of peptides can be variable due to the openness of the HLA2 groove.
Is the number of anchors constant from MHC to MHC?
No, the number of anchors is variable because the number of HLA pockets differ between different HLAs, so the number of peptide anchors must vary
What part of the HLA binds to the antigenic protein?
the HLA pocket binds the antigenic sequence motif “anchor”
What factors are different from HLA pocket to HLA pocket?
size, charge and shape
How many different peptides can each HLA allele bind?
1000-10,000 different peptides that are STRUCTURALLY RELATED
If a cell is infected, what will be in the majority of HLA molecules?
Self peptides still, but one or a few will show the non-self (like recognizing a pimple on a generally flawless face, the non-self will stick out despite the majority being self)
Where are HLA-1 molecules located? Why?
On pretty much all nucleated cells (everywhere except RBCs) because HLA1 remove edogenous pathogens (like viruses)
Why are there no HLA1 molecules on RBCs?
Because RBCs can’t support viral replication anyway so there is no need
Where are HLAII class molecules located?
On macrophages, dendritic cells, B-cells and thymic epithelial cells because they respond to exogenous pathogens and these are the antigen presenting cells
Why are HLAI and HLAII molecules expressed on thymic epithelial cells?
to educate T-cells in thymus to recognize self molecules
On what three cells are HLAII molecules inducible?
endothelial cells
keratinocytes
T cells
What will upregulate MHCI and MHCII?
inflammatory signals like IFNgamma and other cytokines that signal viral infection
How many HLAI and HLAII complexes are expressed on the surface of a healthy cell?
100,000 all loaded with MHC-specific arrays of structurally related self peptides
On what chromosome are the HLAI and HLA II genes located?
HLA1 heavy chain- 6
HLAII - 6
HLA1 light chain- 15
What are the three genes for HLAII?
DP - ab
DQ-ab
DR-ab
All are located on chromosome 6
What the the 4 different genes for HLAI?
B, C and A on chromosome 6
B2M on chromosome 15
What two conformations of antigen can antibodies recognize?
- Linear (continuous)
2. Conformational (discontinuous- which means the protein must be folded in a certain conformation to be recognized)
What is the major function of HLA?
- To signal the presence of a foreign antigen inside the cell and present the antigen to a T cell
- Interact with NK cells to regulate immunity
What type of peptides are TCR able to recognize?
linear peptides that are generated by proteolytic degradation of antigens inside the cell and presented in an HLA molecule
What structure are able to recognize linear and conformational epitopes?
What structure is only able to recognize linear peptides in the context of HLA?
- Antibodies
2. TCR
What are the two main physiological tasks of MHC?
- To activate CD4 and CD8 T cells in response to “non-self” proteins to eliminate pathogens
- To educate CD4 and CD8 T cells in the thymus in response to “self” peptides to prevent autoimmunity
What do CD8 T cells recognize?
What is their function?
small foreign peptides on HLA1 molecules
to kill the cell (usually tumors or pathogen-infected cells)
What do CD4 T cells recognize?
What is their function?
They recognize foreign peptides in HLAII molecules to make cytokines to regulate B cell and macrophage immune response
Because TCR cannot distinguish between HLAI and HLAII, what does it require?
the aid of coreceptors (CD4 and CD8) which bind selectively to invariant portions of the HLAI or HLAII molecules (A3 portion of HLAI and B2 portion of HLAII)
What does it mean that the TCR needs to see the foreign antigenic fragment “in the context of the same HLA on which it was educated”?
It means that the TCR needs to recognize:
- The antigen is foreign
- The HLA is self
If these two things are not true, no action will be taken by the T cell)
What are the two different compartments that deliver antigens to HLAI and HLAII?
- cytosolic-communicates with the nucleus
2. vesicular- continuous with extracellular compartment
What HLA class binds molecules from the cytosol (intracellular compartments)?
Class 1
What HLA class bind molecules from the vesicular compartment (extracellular)?
Class II
Describe the HLA-I ubiquitous pathway.
- Cytosolic proteins (self and non-self) are degraded by proteasomes into peptides
- The peptides are translocated to the ER by TAP peptide transporter
- In the ER, newly synthesized HLAI associates with b2m and the linear peptides
- The HLA molecule with bound peptide travel in a vesicle to to cell surface to present to CD8 T cells
What is the role of TAP (transporter associated with antigen processing and presentation)?
To take degraded peptides from the cytosol into the ER to be bound to the HLA-I molecule
What cells use the HLA-1 ubiquitous pathway?
all nucleated cells that express HLA-1
How is the process of antigen presentation different for HLA-1 molecules in APCs then from other nucleated cells?
- Extracellular antigen is channeled into the cytosol after phagocytosis
- Retrograde transfer takes the antigen from the phagosome to the cytosol
- the steps of the ubiquitous pathway are then followed to present the antigen on HLA-I molecules
What is the “cross presentation pathway”?
What is this pathway important for?
The pathway that allows APCs to express HLA-I molecules to sense extracellular infection in other cell types to activate CD8 to kill the target cells.
This pathway is important for graft rejection
What are the only cells that can efficiently activate naive T cells? Why?
dendritic cells because they can cross-present and upregulate co-stimulatory molecules
What type of antigen does the HLA-II molecule present to T-cells?
What pathway do they use to process and present these antigens?
extracellular antigens
They rely on the vesicular pathway to present antigens in the HLA-II molecule
What is the process HLA-II molecules must go through to present antigen to T-cells?
- Antigen is taken up by endocytosis or phagocytosis
- Cathepsin or other enzymes degrade the antigen in the vesicle
- The HLA-II molecule is made and folded in the ER and associates with an invariant chain (CD74) to occlude the groove
- The HLA-II goes into an endocytic vesicle where the invariant chain is cleaved to CLIP which remains in the groove
- The antigen vesicle meets the HLA-II/CLIP vesicle in the MIIC compartment
- In MIIC, DM molecules replace CLIP with the antigen fragments
- The HLA-II/antigen structure goes to the cell surface and is presented to CD4 T cells
What occludes the HLA-II groove until it can join an antigen?
CD74 invariant chain which gets degraded to CLIP fragment
Where does the antigen vesicle and HLA-II/CLIP complex vesicle collide?
MIIC
What happens in the MIIC vesicle?
DM replaces the CLIP fragment with antigen fragments to be presented to the cell surface
What serves as a signal for NK molecules that all is not well within the cell?
The HLA-I molecule indicates that there is something wrong with the cell because pathogens will attempt to downregulate class I MHC to escape being killed by CD8 Tcells
What two receptors are found on NK cells?
Why?
There is an activating receptor and an inhibitory receptor.
The activating receptor (NKG2D) wants to kill the cell really badly, but the inhibitory receptor (KIR) will block this action if there is a positive healthy HLA-I.
When a tumor or virus downregulates HLA-I presentation as a subversion mechanism, what happens?
The T cell is no longer able to recognize the cell, but the NK cell will kill it because the KIR will not bind HLA and inhibit NKG2D activating receptoc
What HLA-like molecule presents glycolipids and non-peptide self and foreign antigens?
CD1
What chromosome encodes CD1 molecules?
chromosome 1 (not on the HLA chromosome) But they associate with B2M (chromosome 15)
How are the antigens presented by CD1 different from those presented on HLA?
- non-peptide
2. non-fragemented (unprocessed)
How is the antigen binding groove of CD1 different from HLA?
narrower and hydrophobic to accommodate lipid antigens
Where are lipids and glycolipids loaded into CD1 grooves?
in endocytic compartments (similar to MIIC where peptides are loaded into HLA-II)
What is a superantigen?
It is a microbial protein like staphylococcal enterotoxin or toxic shock syndrome toxin-1 that bridges the variable B domain of TCR to the HLA-II molecule.
This stimulates a massive release of cytokines which are toxic
What causes staphylococcus enterotoxin to get into the body?
food poisioning
What is bare lymphocyte syndrome (BLS)?
What is the most common deficiency in HLA-I BLS?
What is the most common deficiency in HLA-II BLS?
A syndrome associated with the loss of HLA-I and HLA-II molecules.
The most common deficiency in HLA-I BLS is TAP loss.
HLA-II BLS–> inactivation of transcription complex for the HLA-II genes
Why would BLS result in a reduced number of CD4 and CD8 Tcells?
because there is a reduced number of HLA-I or HLA-II molecules and so the T cells aren’t educated in the thymus
Which deficiency is worse, HLA-I or HLA-II?
HLA-II deficiency is worse because it educates CD4 T cells which are helper cells necessary for CD8 T-cell response as well as dendritic and macrophage activation
