Lec 10: MHC I and NK cells Flashcards

1
Q

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

A

Class 1 MHC
Class 2 MHC
Class 3 MHC

-> Complement and inflammation protein

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2
Q

Structure of the MHC I molecule

a chain

A

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

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3
Q

Structure of the MHC I peptide binding domain

-> leads to // allows polymorphism

A

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

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4
Q

promiscuety of MHC1 molecules

A

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

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5
Q

What does TcR recgnize of the MHC 1 complex

A

sequence and structure

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6
Q

Allelic variation of the MHC complex in humans

A

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

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7
Q

Purpose of co-dominant expression of alleles

A

increased the overall diversity of alleles for MHC

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

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8
Q

MHC 1: HLA-B

A

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

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9
Q

Differentiation of the MHC locus at the species level

A

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 )

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10
Q

Do presented antigens truly represent self?

A

????

except with cross-presentation by CD8 CD’s

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11
Q

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

A

intracellular antigen peptides

  • self-proteins
  • viral infection
  • abnormal proteins from things like cancer
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12
Q

Purpose of MHC I antigen processing

A

provides a way for checking that cells are generally healthy

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13
Q

Where is MHCI peptide expression found

A

in all nucleated cells

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14
Q

What type of cells are MHCI peptides presented to

A

CD8+ T cells

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15
Q

How are peptides made during MHC class I antigen processing

A

proteosome recycles defective ribosomal products (DRiPs) and mature proteins

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16
Q

Note: MHC expression can change with changing conditions

A

yupp

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17
Q

modulation of MHC I expression

A

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

Responsive promoters modulate transcription of MHC genes

18
Q

Viral interference of MHC I antigen processing

A

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

19
Q

What happens is cells do not express MHC

A

normal healthy cells always express MHCI

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

20
Q

Natural killer (NK) cells

A

recognize the absence of MHCI

Important for killing tumor cells and virus-infected cells

express DC56+

21
Q

NK cell-mediated effector responses

A

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)

22
Q

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

A

both!

respond quicker that CD8 cells

23
Q

Do NK cells have memory?

A

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

24
Q

Anergy

A

a hyporesponsive state

deactivated NK cells that don’t recognize MHC

25
Q

NK cell selection in the bone marrow

A

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

26
Q

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

A

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

27
Q

Phenotype of NK cells

A

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

human NK cells lack NK1.1 but express CD56

28
Q

The “Missing-self” model

A

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

29
Q

The “Balanced signals” model

A

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

30
Q

Read ch 12, fig 12-15

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

A

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.

31
Q

NK cell Killing

A

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

32
Q

Mechanism of NK cell killing

A

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

33
Q

NK cells lay the SMAC down for killing

A

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

34
Q

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

A

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

35
Q

NK cell memory

A

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
36
Q

NK cells possess antigen-specific receptors

A

example = Ly49H binds murine CMV glycoprotein on infected cell surface

37
Q

NK cells undergo clonal expansion during infection

A

clonal expansion is antigen driven

38
Q

NK cells can generate long-lived memory cells

A

memory NK cells have unqiue transcriptional signature

39
Q

NK vs NK T cells

A

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

40
Q

HLA-G is a non-classical MHC I molecule

A

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

41
Q

HLA-G heavy chain

A

heavy chain is non-covalently associated with b2-microglobulin

42
Q

HLA-G is a tolerogenic moleucle

A

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