Lecture 31 - NK Cells Flashcards
How were NK cells first observed?
Lymphocytes in mice were observed to kill tumour cells
Adherent cells in the spleen
Macrophages
Surface markers identifying T cells
CD3, TCR
NK cell identifying surface markers 1) 2) 3) 4) 5)
1) CD3/TCR -
2) Surface IG -
3) CD161 (NK1.1) +
4) CD56 +
5) CD16 can be present, but not always
NKT cell identifying surface markers
1)
2)
3)
1) CD3/TCR +
2) Surface IG -
3) CD161 (NK1.1)
Features of NK cells 1) 2) 3) 4)
1) Innate lymphocytes
2) Lack antigen-specific Ig receptors
3) Express a number of receptors that control activation
4) Thought not to undergo clonal expansion, but this is being challenged
Time after viral infection that NK response peaks
~3 days
Cytokine that induces NK response
IFNg
NK cell functions
1)
2)
3)
1) Lysis of target cells (perforin, granzymes, Fas/FasL)
2) Secrete cytokines (IFNg, TNFa)
3) Secrete chemokines
Things that can activate NK cells
1)
2)
3)
1) Cytokines (IL-12, IL-15, IL-18, IFNg)
2) Cellular interactions (antibody-dependent cellular cytotoxicity)
3) Natural cytotoxicity
Antibody-dependent cellular cytotoxicity 1) 2) 3) 4)
1) IgG binds to target cell
2) IgG detected by CD16 (FcgRIII) on NK cell
3) CD16 is associated with a CD3-like adaptor that has ITAMS
4) Lysis of cell
Natural cytotoxicity
1)
2)
3)
1) An innate ability of NK cells, doesn’t require antibodies
2) Kills virus-infected cells
3) MHCI inhibits NK cell activation. NK cell inspects target cell, if target cell lacks MHCI, killed
Cells susceptible to NK lysis
1)
2)
1) Some viruses downregulate MHCI expression to avoid CD8+ detection. NK cells kill these
2) Tumour cells often have defective MHCI
Viruses that interfere with MHCI expression
1)
2)
3)
1) Cytomegalovirus
2) Herpes simplex virus
3) HIV
3 types of inhibitory receptors in NK cells
1) Ly49
2) Killer-cell immunoglobulin-like receptors (KIR, CD158)
3) CD94/NKG2A
Ly49
1)
2)
3)
1) Inhibitory receptor expressed by rodent NK cells
2) Members of C-type lectin superfamily
3) Recognise H-2D, H-2K class I molecules
Killer cell immunoglobulin-lie receptors (KIR) 1) 2) 3) 4)
1) Expressed by primate NK cells
2) Family of receptors (CD158a-f)
3) Members of Ig-like superfamily
4) Recognise HLA-B (Bw4) and HLA-C MHCI molecules (and some HLA-A)
MHCI molecules recognised by KIR
HLA-B (Bw4), HLA-C, some HLA-A
CD94/NKG2A
1)
2)
3)
1) Highly conserved through evolution
2) Members of C-type lectin superfamily
3) Recognises non-classical MHCI (HLA-E in humans)
4) Ubiquitous expression, non-polymorphic (only 2 alleles in human population)
What do NK inhibitory receptors signal thorough?
ITIMs (Immunoreceptor tyrosine–based inhibitory motifs)
Ly49 ITIM configuration
Ly49 is a dimer, one ITIM per cytosolic part of Ly49 monomer
CD158 ITIM configuration
2 ITIMs per cytosolic region of CD158
CD158
Killer cell immunoglobulin-like receptor (KIR)
Another name for killer cell immunoglobulin-like receptor
CD158
How do NK inhibitory receptors signal?
1)
2)
3)
1) Receptor is bound
2) ITIM Is phosphorylated
3) SHIP is activated, which prevents NK cell activation
Different forms of killer cell immunoglobulin-like receptor 1) 2) 3) 4)
1) Have either 2 or 3 extracellular domains
2) Are either S or L form (short cytoplasmic tail or long cytoplasmic tail form)
3) S forms lack ITIMs. L forms have ITIMs.
4) S lack ITIMs, so aren’t actually inhibitory receptors
What do different domain-types of killer cell immunoglobulin-like receptors do?
Detect different HLA types
CD158a
2DL1
CD158b
2DL2/3
What do killer cell immunoglobulin-like receptors 2DL1 and 2DL2/3 detect?
HLA-C group 1 and 2
What does CD158a detect?
HLA-C group 2
What does CD158b detect?
HLA-C group 1
Which NK cell receptor detects Bw4?
KIR 3DL1
What does KIR 3DL1 detect?
Bw4
What does KIR 3DL2 detect?
A3/A11
Which NK cell receptor detects HLA A3/A11?
KIR 3DL2
Number of MHCI epitopes recognised by KIR
4
These are mutually exclusive. A MHCI can only be one of these types
MHCI epitopes recognisable by KIR 1) 2) 3) 4)
1) Group 1 HLA-C (or C-1)
2) Group 2 HLA-C (or C-2)
3) Bw4
4) A3/A11
Do all HLA alleles possess either C1, C2, Bw4 or A3/A11 determinants?
No.
This is thought to minimise competition between CD8+ and NK cells
HLA types that often don’t possess NK-recognised epitopes
HLA-A and HLA-B
HLA alleles that KIR mostly recognises
HLA-C
What defines Bw4/Bw6 HLA-B alleles?
1)
2)
1) Specific amino acid sequence between amino acids 77 and 83.
2) This sequence lies within the alpha-helix which makes up part of the binding groove of HLA-B
What defines C1 and C2 HLA-C alleles?
Amino acid 80 asparagine or lysine
KIR HLA binding site
On the join between the two Ig-like domains of the protein
Where on an MHCI molecule do KIR normally bind?
The edges
Is there variation in which inhibitory receptors NK cell express?
Yes.
Why might it be beneficial for NK cells to express different inhibitory molecules? 1) 2) 3) 4)
1) Some viruses (EG: HIV with nef) inhibit the expression of some MHCI alleles (HIV inhibits HLA-A, HLA-B, doesn’t affect HLA-C)
2) Some NK cells will be inhibited by HLA-C expression, but some NK cells lack inhibitory receptors for HLA-C
3) These NK cells will be able to kill HIV-infected cell
4) Normal cells express HLA-A, HLA-B and HLA-C, so aren’t killed by NK cells
Allele of NK surface receptor that results in delayed progression to AIDS
1)
2)
1) Bw4
2) Nef-mediated downregulation of Bw4 leads to killing of infected cells
Effect of allotype on acute myeloid leukaemia patients
If there is a KIR-ligand mismatch between patient and bone-marrow donor, then NK cells are produced that kill tumour cells
KIR that recognises HLA-Bw4
CD158e
