Lecture 6: Innate Responses to Infection: Natural Killer Cells

Question 1

What are NK cells?

Answer 1

part of the ILC (innate lymphoid cells) family of cells

Question 2

What does the development of NK cells require?

Answer 2

Id2, Nfil3 and eomesodermin (eomes)

presence of IL-15

Question 3

How are NK cells distinguished?

Answer 3

lack Ag-specific receptors (i.e. TCR, slg)
not many receptors are uniquely expressed by NK cells
most commonly used combination is CD56+ CD3-

Question 4

How do NK cells kill?

Answer 4

lyse target cells by releasing cytotoxic granules

-> perforin/granzyme dependent

Question 5

What is TRAIL?

Answer 5

TNF related apoptosis inducing ligand -> interacts with DR4 and DR5 (death receptors)

Question 6

What does engagement of DR4/DR5 lead to?

Answer 6

activation of caspase 8 and apoptosis

Question 7

What are the key roles of NK cells?

Answer 7

immunity to viral infections and tumours

emerging role in reproduction

Question 8

What do NK cells secrete?

Answer 8

cytokines e.g. IFNy, TNFa

chemokines e.g. XCL1

Question 9

What turns on a NK cell?

Answer 9

cytokines -> type I interferons, IL-12, IL-15, IL-18
cellular interactions -> antibody dependent cellular cytotoxicity (CD18)
natural cytotoxicity -> role of MHC class I and MHC-class I-like proteins

Question 10

What is NK cell activity controlled by?

Answer 10

a balance of stimulatory and inhibitory signals

Question 11

Which molecules activate NK cells?

Answer 11

FcR, NKG2D

activating siblings: KIR, NKG2C, Ly49, LILR

Question 12

Which molecules inhibit NK cells?

Answer 12

inhibitory siblings: KIR, NKG2A, Ly49, LILR

Question 13

What does antibody dependent cellular cytotoxicity require?

Answer 13

requires antibody (i.e. adaptive immune response) and CD16 (FcyRII)

Question 14

What is CD16 (FcyRIII) associated with?

Answer 14

a “CD3”-like adaptor that contains ITAMS

Question 15

Why don’t NK cells kill “normal” cells?

Answer 15

because “normal” cells express class I

Question 16

Which receptors bind MHC class I?

Answer 16

inhibitory receptors -> prevents activation of NK cells

Question 17

What are examples of susceptibility to NK cell lysis?

Answer 17

virus infection e.g. HSV, CMV can downregulate MHC class I expression
tumour cells frequently have defective class I expression

Question 18

What are Ly49 receptors expressed by and what are they members of?

Answer 18

expressed by rodent NK cells
members of the C-type lectin superfamily
recognise H-2K and H-2D class I molecules

Question 19

What are CD94/NKG2A receptors expressed by and what are they members of? What do they recognise?

Answer 19

expressed by both rodent and primate NK cells
members of the C-type lectin superfamily
recognises non classical MHC class I molecules

Question 20

What do CD94/NKG2A receptors recognise in humans and mice?

Answer 20

HLA-E (humans)
Qa-1^b (mice)
ubiquitous expression, not polymorphic

Question 21

What is significant about HLA-E/Qa-1?

Answer 21

have peptide binding clefts specialised for presenting conserved peptides present in the signal sequence of other MHC class I proteins

Question 22

What happens if a virus or tumour disrupts the expression of HLA-A, HLA-B or HLA-C?

Answer 22

there is a decrease in the amount of peptide entering the cell and interacting with HLA-E which results in a drop in HLA-E levels at the cell surface and a decrease in inhibitory signalling on the NK cell through CD94-NKG2A

Question 23

What are killer cell immunoglobulin-like receptors (KIR) expressed by and what are they members of?

Answer 23

expressed by primate NK cells
members of the Ig-superfamily
recognise groups of HLA-A, -B and -C allotypes (HLA-C > HLA-B > HLA-A)

Question 24

Which four epitopes present on groups of class I molecules does KIR recognise?

Answer 24

C1 (or group 1 HLA-C)
C2 (or group 2 HLA-C)
Bw4
A3/A11

Question 25

Why could the four epitopes recognised by KIR present on groups of class I molecules be a requisite for survival of the population?

Answer 25

despite significant differences in HLA alleles present in distinct ethnic groups, all populations studied to date possess alleles from each group

Question 26

How does KIR bind to HLA?

Answer 26

``` uses interdomain "elbow" regions to bind to HLA KIR binds over the C-terminal region of the peptide and the alpha 1 and 2-helices of the HLA class I ```

Question 27

What impacts recognition by KIR?

Answer 27

the sequence of the peptide bound to the HLA class I protein

Question 28

What is the role of unlicensed cells?

Answer 28

respond during acute viral infection | role for pro-inflammatory cytokines

Question 29

What happens if HLA is not present on the cell (due to downregulation)?

Answer 29

NK cells are activated because there is no inhibitory signal

Question 30

What is NKG2D?

Answer 30

activating receptor which is expressed by all NK and certain T cell subsets

Question 31

What are characteristics of NKG2D ligands?

Answer 31

``` MHC class I-like molecules do not bind peptides do not associate with B2 microglobulin ```

Question 32

What are examples of NKG2D ligands?

Answer 32

human -> MIC-A/B and ULBP (UL16 binding proteins) | mice -> RAE-1 (retinoic acid early inducible transcripts) and H60

Question 33

How are NKG2D ligands regulated?

Answer 33

non constitutive -> low or absent in most adult tissues inducible -> heat shock, viral infection, bacterial infection frequently expressed on tumours/transformed cells

Question 34

What does expression of NKG2D ligands indicate?

Answer 34

cellular stress -> infected/transformed cells

Question 35

What is NKG2D ligand expression initiated by?

Answer 35

protein kinases ATM or ATR | induced as a result of DNA damage e.g. cleaved dsDNA or stalled replication forks