Lec 10: MHC I and NK cells

Question 1

Which classes of genes does the MHC locus on Chromosome 6 encode

Answer 1

Class 1 MHC
Class 2 MHC
Class 3 MHC

-> Complement and inflammation protein

Question 2

Structure of the MHC I molecule

a chain

Answer 2

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

Question 3

Structure of the MHC I peptide binding domain

-> leads to // allows polymorphism

Answer 3

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

Question 4

promiscuety of MHC1 molecules

Answer 4

a given MHC molecule can bind numerous different peptides and some peptides can bind to several different MHC molecules

Question 5

What does TcR recgnize of the MHC 1 complex

Answer 5

sequence and structure

Question 6

Allelic variation of the MHC complex in humans

Answer 6

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

Question 7

Purpose of co-dominant expression of alleles

Answer 7

increased the overall diversity of alleles for MHC

this diversity provides flexibility in responding to unexpected environmental changes, now and in the future

Question 8

MHC 1: HLA-B

Answer 8

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

Question 9

Differentiation of the MHC locus at the species level

Answer 9

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 )

Question 10

Do presented antigens truly represent self?

Answer 10

????

except with cross-presentation by CD8 CD’s

Question 11

What kind of peptides does MHC I present? Where are they from?

Answer 11

intracellular antigen peptides

• self-proteins
• viral infection
• abnormal proteins from things like cancer

Question 12

Purpose of MHC I antigen processing

Answer 12

provides a way for checking that cells are generally healthy

Question 13

Where is MHCI peptide expression found

Answer 13

in all nucleated cells

Question 14

What type of cells are MHCI peptides presented to

Answer 14

CD8+ T cells

Question 15

How are peptides made during MHC class I antigen processing

Answer 15

proteosome recycles defective ribosomal products (DRiPs) and mature proteins

Question 16

Note: MHC expression can change with changing conditions

Answer 16

yupp

Question 17

modulation of MHC I expression

Answer 17

some cytokines expressed during infection/ disease can drive up/ down MHC expression

Responsive promoters modulate transcription of MHC genes

Question 18

Viral interference of MHC I antigen processing

Answer 18

Viruses like to shut down MHC I expression as an immune evasion mechanism

Question 19

What happens is cells do not express MHC

Answer 19

normal healthy cells always express MHCI

NK cells recognize the absence of MHC I and will induce that cell to undergo apoptosis

Question 20

Natural killer (NK) cells

Answer 20

recognize the absence of MHCI

Important for killing tumor cells and virus-infected cells

express DC56+

Question 21

NK cell-mediated effector responses

Answer 21

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)

Question 22

Are NK cells a part of the innate or adaptive immune response

Answer 22

both!

respond quicker that CD8 cells

Question 23

Do NK cells have memory?

Answer 23

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

Question 24

Anergy

Answer 24

a hyporesponsive state

deactivated NK cells that don’t recognize MHC

Question 25

NK cell selection in the bone marrow

Answer 25

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

Question 26

How does the balance between activating and inhibition signals determine the NK cell state

Answer 26

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

Question 27

Phenotype of NK cells

Answer 27

mouse NK cells typically express CD 122, NK1.1, CD2, FcgammaRIII and CD49b

human NK cells lack NK1.1 but express CD56

Question 28

The “Missing-self” model

Answer 28

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

Question 29

The “Balanced signals” model

Answer 29

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

Question 30

Read ch 12, fig 12-15

Tolerance vs The missign self model vs summation of receptors on NK cells

Answer 30

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.

Question 31

NK cell Killing

Answer 31

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

Question 32

Mechanism of NK cell killing

Answer 32

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

Question 33

NK cells lay the SMAC down for killing

Answer 33

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

Question 34

NK cells are more potent than CD8+ T cells in terms of cytotoxicity and cytokine secretion

Answer 34

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

Question 35

NK cell memory

Answer 35

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

Question 36

NK cells possess antigen-specific receptors

Answer 36

example = Ly49H binds murine CMV glycoprotein on infected cell surface

Question 37

NK cells undergo clonal expansion during infection

Answer 37

clonal expansion is antigen driven

Question 38

NK cells can generate long-lived memory cells

Answer 38

memory NK cells have unqiue transcriptional signature

Question 39

NK vs NK T cells

Answer 39

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

Question 40

HLA-G is a non-classical MHC I molecule

Answer 40

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

Question 41

HLA-G heavy chain

Answer 41

heavy chain is non-covalently associated with b2-microglobulin

Question 42

HLA-G is a tolerogenic moleucle

Answer 42

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