Lec 10: MHC I and NK cells Flashcards
Which classes of genes does the MHC locus on Chromosome 6 encode
Class 1 MHC
Class 2 MHC
Class 3 MHC
-> Complement and inflammation protein
Structure of the MHC I molecule
a chain
three external domains, and a transmembrane domain.
there exists a cytoplasmic anchor
the a1 and a2 domains form a cleft region that binds 8-10aa long peptide fragments from antigens
a b sheet forms the floor of the cleft
two a helixes form the walls
Structure of the MHC I peptide binding domain
-> leads to // allows polymorphism
some aa anchor the peptide into the groove
other aa are available to interact with a TcR
peptide binding domain a1/a2
peptide grove closed at both ends -> this limits the peptide size to 8-10 aa
promiscuety of MHC1 molecules
a given MHC molecule can bind numerous different peptides and some peptides can bind to several different MHC molecules
What does TcR recgnize of the MHC 1 complex
sequence and structure
Allelic variation of the MHC complex in humans
MHC complex is the most highly polymorphic region in the entire genome
allelic forms of MHC are inherited in linked groups called Haplotypes
one haplotype from the mother and one haplotype from the father
Purpose of co-dominant expression of alleles
increased the overall diversity of alleles for MHC
this diversity provides flexibility in responding to unexpected environmental changes, now and in the future
MHC 1: HLA-B
is a major presenter of peptides
A) shows the frequency of HLA alleles >3% in a human population
B) shows the number of peptides that were found to associate with a given allele
Differentiation of the MHC locus at the species level
organization of MHC locus differs in mice and humans
polygenic diversity is different
in humans, 6 unique classical MHC1 molecules per cell, there is also 6 in mice (3 from both the paternal and maternal lineage )
Do presented antigens truly represent self?
????
except with cross-presentation by CD8 CD’s
What kind of peptides does MHC I present? Where are they from?
intracellular antigen peptides
- self-proteins
- viral infection
- abnormal proteins from things like cancer
Purpose of MHC I antigen processing
provides a way for checking that cells are generally healthy
Where is MHCI peptide expression found
in all nucleated cells
What type of cells are MHCI peptides presented to
CD8+ T cells
How are peptides made during MHC class I antigen processing
proteosome recycles defective ribosomal products (DRiPs) and mature proteins
Note: MHC expression can change with changing conditions
yupp
modulation of MHC I expression
some cytokines expressed during infection/ disease can drive up/ down MHC expression
Responsive promoters modulate transcription of MHC genes
Viral interference of MHC I antigen processing
Viruses like to shut down MHC I expression as an immune evasion mechanism
What happens is cells do not express MHC
normal healthy cells always express MHCI
NK cells recognize the absence of MHC I and will induce that cell to undergo apoptosis
Natural killer (NK) cells
recognize the absence of MHCI
Important for killing tumor cells and virus-infected cells
express DC56+
NK cell-mediated effector responses
make up 5-10% of circulating lymphocytes
help to regulate innate/ adaptive immunity by cytokine secretion
recognize and destroy pathogen-infected cells and abnormal tumor cells
Proliferate earlier in infection than cytotoxic CD8+ T cells (CTLs)
Are NK cells a part of the innate or adaptive immune response
both!
respond quicker that CD8 cells
Do NK cells have memory?
Dont think so?
Lack specific antigen receptors and memory?
-> this has been recently disputed as LY49H/ NKGC2 receptor can bind CMV
Memory NK cells have been identified
Anergy
a hyporesponsive state
deactivated NK cells that don’t recognize MHC
NK cell selection in the bone marrow
NK cells are lympoid cells derived from the CLPs in the bone marrow
Developing NK cells selected by interactions with stromal cells in bone marrow
Licensing: don’t automatically possess killing potential, unless prior interaction with a healthy cell through MHC class I/ inhibitory receptor
How does the balance between activating and inhibition signals determine the NK cell state
NK cells recognize and kill infected cells and tumor cells by their absence of MHC I
Defining trait is the expression of a set of activating and inhibiting NK receptors
-> sum of receptor signaling determines whether to kill a target or not
Phenotype of NK cells
mouse NK cells typically express CD 122, NK1.1, CD2, FcgammaRIII and CD49b
human NK cells lack NK1.1 but express CD56
The “Missing-self” model
Normal cells present a ligand for teh activating (Killing) receptor on NK cells
and
a ligand for the inhibitory receptor (Class I MHC serves as thsi second ligand)
When virsues infect cells, some may inhibit MHC class I expression to evade detection and elimination by CTLs
The “Balanced signals” model
Tumor cells may lose the expression of MHCI
-> Difficult for CTLs to detect, but prime targer for elimination by NK cells
Stressed cells may upregulate activating ligands for NK cells, which can also lead to tumor elimination
Read ch 12, fig 12-15
Tolerance vs The missign self model vs summation of receptors on NK cells
green star
The balance
of signals from activating and inhibitory receptors determines whether an NK cell will kill a target cell.
(a) Tolerance: no killing. An
activating receptor on NK cells interacts with its ligand on normal cells, inducing an activation signal. However, engagement of
inhibitory NK-cell receptor(s) by self MHC class I molecules delivers inhibitory signals that counteract the activation signal, and the
cell is not killed.
(b) Missing self model. Because MHC class I expression is often decreased on altered self cells, such as virus-infected and tumor cells, the activating signal predominates, leading to target cell destruction.
(c) As some cells that are killed by NK cells are
not always MHC class I-negative and express multiple activating and inhibitory receptors, the balanced signals model was
developed. Infected, stressed, or tumor cells up-regulate expression of certain proteins that are recognized by activating receptors
on the NK cell. If the activating signals are more extensive than inhibitory receptors, the NK cell becomes activated.
NK cell Killing
NK cells induce the apoptosis of their targets
-> Recall that the induction of apoptosis helps the body to avoid unessecary immune response/ activation
once activating signal molecules are engaged, NK cells use mechanisms very similar to CTLs to induce target cell death
Mechanism of NK cell killing
release of perforins/ granzymes at teh junction of the two cells
- > granzymes enter through pores made from perforins
- > activaiton of caspase-1 to to induce apoptosis
engage death receptors on target cell
secrete IFNy to induce MHC I on target cell surface for CTL detection
NK cells lay the SMAC down for killing
forming a SMAC allows for the NK cell to directly transfer cytotoxic mediators to the target cell
Perforin: punctures holes in the target cell membrane
Granzyme B: cytotoxic molecule inducing apoptosis in target cell
NK cells are more potent than CD8+ T cells in terms of cytotoxicity and cytokine secretion
less specific an more potent
super important in early infection
T cells clean up later with specific targets
this is benifical because it will minimize tissue damage later in infection
NK cell memory
NK cells have been classified as a component o the innate immune system
However, accumulating evidence in mice and humans suggests that, like B cells and T cells of the adaptive immune sytem NK cells:
- > are educated during development
- > possess antigen-specfic receptors (bind vial proteins)
- > undergo clonal expansion during infection
- > generate long-lived memory cells
NK cells possess antigen-specific receptors
example = Ly49H binds murine CMV glycoprotein on infected cell surface
NK cells undergo clonal expansion during infection
clonal expansion is antigen driven
NK cells can generate long-lived memory cells
memory NK cells have unqiue transcriptional signature
NK vs NK T cells
NK cells express a limited sett of invariant activating and inhibitory receptors
- > they detect the absence of MHC I
- > provoke an immediate response
NK T cells express semi-invariant TcR taht interacts with CD1 molecules
-> CD1 presents lipid (not peptide) antigens
HLA-G is a non-classical MHC I molecule
THis means it does not present peptides and instead acts as an inhibitory receptor like on NK cells
HLA-G is similar to classical HLA class I molecules
does not bind TcR, interacts with inhibitory receptors
HLA-G heavy chain
heavy chain is non-covalently associated with b2-microglobulin
HLA-G is a tolerogenic moleucle
helps to modulate the immune response
- inhibits CTLs
- –> this helps to protect the fetus from cytoxic immune response
- inhibits NK cells
- induction of tolerogenic APCs
restricted tissue expression
- placental tissues
- cancer cells
- autoimmune disease
- viral infections
- —> immune invasion (NK and T cells) cannot kill
