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MIIM30002 - Principles of Immunology > Lecture 31 - NK Cells 1 > Flashcards

Lecture 31 - NK Cells 1 Flashcards

1
Q

When were NK cells discovered?

What were the initial observation?

A

1975

Observations:
Cells that could kill tumour cells

Normal mice, non immunised
Contain cells that kill the leukaemia cells
Killing activity
Spleen had more of the activity
LN and BM a little
Thymus none
Indicated the location of these cells

Treatment with anti-Thy-1 serum, as well as removal of adherent and surface Ig positive cells from spleen enriches the activity (ie removing T cells, macrophages and B cells)

The remaining cells had the morphology of small lymphocytes

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2
Q

What are NK cells also called?

A

Large granular lymphocytes

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3
Q 
Compare the following cells:
 • T cells
 • B cells
 • NK cells
 • NK T cells
A

T cells:
• CD3/TCR+

B cells:
• Surface Ig+

NK cells:
• CD3/TCR-
• Surface Ig-
• CD161 + (aka NK1.1+)

  • CD56+ (also variable)
  • CD16 (+/-)

NK T cells:
• CD3/TCR+
• Surface Ig-
• CD161+

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4
Q

What is CD161?

A

Surface antigen initially found to be on NK cells

aka NK1.1

“NK-type receptors”

Also found on NK T cells

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5
Q

What is the difference between NK T cells and NK cells?

Which arm of the immune response are they?

A

NK T cells:
• Express CD3/TCR
• Innate-like response
• Differentiate from DP thymocytes in the thymus

NK cells:
• Do not express CD3/TCR
• “Induced” innate response
• Differentiate from CLP in BM

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6
Q

Describe the major features of NK cells
• Main marker
• Function

A
  • Lymphocytes
  • CD3/TCR-
  • Surface Ig-
  • Express an array of receptors that control their activation

Main marker:
• NKp46

Function:
• Respond to a variety of viruses and tumours
• Do not undergo clonal expansion following infection (this was the dogma, but it’s currently under revision)

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7
Q

Which pathogens do NK cells respond to?

A

Viruses

Not bacteria

NB also respond to tumours

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8
Q

What is NK1.1?

A

CD161

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9
Q

What is the main marker of NK cells?

A

NKp46

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10
Q

What activates NK cells?

A
  1. Cell surface interactions
    • CD16 (FcγRIII) → ADCC
  2. Cytokines
    • Type I interferon
    • IL-12, IL-15, IL-18
  3. Natural cytotoxicity
    • Missing self recognition of virally infected cells
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11
Q

Describe the effector function of NK cells

A
  1. Lysis of cells
    • Perforin/Granzyme dependent
    • Fas/FasL
  2. Cytokine secretion
    • IFN-γ
    • TNF-alpha
  3. Chemokine secretion

Thus, they are kind of like effector memory cells

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12
Q

What is CD16?

Where is it found?

A

FcγRIII
Found on the surface of NK cells (in humans)

CD3-like adaptor that contains ITAMs

When engaged it leads to ADCC

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13
Q

Describe Natural cytotoxicity

A

• “Missing self” hypothesis

• Direct recognition of virus infected cells or tumours
( • No Ab required, thus purely innate)

NK cell receptors:
• Activation receptors
• Inhibitory receptors; recognise MHC I

Signals:
• MHC I inhibition signal, uniquitous on healthy cells
• Activation signal; ubiquitous on all cells, or, in the case of NKG2D, can be up-regulated in conditions of cell stress

Process:
1. NK cells interrogate target cells through activation and inhibitory receptors

  1. Normally inhibitory receptor interaction with MHC I is dominant (?) and and activation signals (uniquitously present) are blocked

– viral infection –

  1. Down regulation of MHC I by virus (HSV, CMV, tumours, HIV)

– loss of MHC I –

  1. Predominance of activation signal
  2. Lysis of target cell
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14
Q

Describe ADCC with NK cells

A

CD16 (FcγRIII) associated with a CD3-like adaptor that contains ITAMs

  1. Infected cell bound with Ab
  2. FCγRIII (CD16) on NK cell binds Ab
  3. Cross linking of receptors
  4. Activation / clustering of ITAMs
  5. Intracellular transduction pathway
  6. Induction of cytotoxicity:
    • Granzymes, Perforin, Serglycin
  7. Target cell lysis
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15
Q

Discuss the inhibitory receptors
• Where they are expressed
• Superfamily
• What they recognise

A

3 types

  1. Ly49 receptors
    • In rodents
    • Expressed by rodent NK cells
    • Family of receptors: C-type lectin superfamily (do not bind sugars though)
    • Recognise classical rodent MHC I molecules (H-2K, H-2D)
2. Killer cell Immunoglobulin-like receptors (KIR) (CD158)
 • In primates
 • Primate NK cells
 • Members of Ig-superfamily
 • Recognise HLA-C & HLA-B (ie class I)
3. CD94/NKG2A
 • In rodents and primates (conserved through evolution)
 • Members of C-type lectin superfamily
 • Recognises non-classical MHC class I
- HLA-E (in humans)
- Qa-1(b) (in mice)
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16
Q

What is HLA-E?

A

Non-classical HLA in humans

Different from classical in that they are not polymorphic
There are only two alleles in the human population, differing by one amino acid
Both alleles are 50%
AA change doesn’t change the specificity of the receptor-ligand interaction

17
Q

Describe, in general, signalling through inhibitory receptors on NK cells

A

ITIMs: motifs on the intracellular portion of receptors (ie Ly49 and CD158)

1. Ly49
Killer cell Immunoglobulin-like receptors (KIR) 
 • Dimer
 • One ITIM on each subunit
 • YxxV
  1. CD158 / KIR
    • Monomer
    • Two ITIMs per tail
    • YxxL
  2. Engagement of ligands
  3. Tyrosine residues in ITIMs becomes phosphorylated
  4. Recruitment of phosphatase called SHIP
  5. Blockage of further activation (ie NK cell turned off, because the cell isn’t infected)
18
Q

What is CD158?

A

NK inhibitory receptor only found in humans

aka Killer cell Immunoglobulin-like receptors (KIR)

19
Q

Describe the different types of KIR receptors

A

Various ‘flavours’:
• Long/short cytoplasmic tails: L / S
• 2/3 domains: 3D / 2D

‘L’ and ‘S’ forms
• L forms have ITIMs and long cytoplasmic tails
• S: short cytoplasmic tail, no ITIMs

Domains
• 2D: two domains
• 3D: three domain

eg
• 2DL1
• 3DL2

20
Q

Which KIR molecules have ITIMs?

A

‘L’ forms, ie those with long cytoplasmic tails

21
Q

Describe signalling through KIR

A

2DL1, 2DL2 & 2DL3 most important

  1. Engagement of 2DL1 / 2DL2 / 2DL3 recognise subgroups of the HLA-C locus
  2. Phosphorylation of ITIMs
  3. Inhibition of NK cell
22
Q

What do KIR receptors recognise?

Describe some features

A

Epitopes / regions on certain MHC class I molecules

Properties:
1. Mutually exclusive
• A given HLA allele can not be A3 as well as A11 etc.
• They are all completely independent
2. These epitopes are not found on all HLA alleles (eg mostly only found on HLA-C)

Properties shared by clusters of HLA alleles

2DL1, 2DL2 & 2DL3:
 • Subgroups of the HLA-C locus:
 • Group 1 and Group 2 alleles:
ie
- HLA-C1
- HLA-C2

3DL2:
• HLA-A3
• HLA-A11

3DL1:
• HLA-Bw4

23
Q

Compare the ‘function’ or use of the various HLA groups

A

HLA-A & HLA-B
• Most important for priming T cell responses

HLA-C
• More important for controlling NK cell responses

NB HLA-A3/11 probably evolutionary remnants

24
Q

Describe KIR epitopes within different ethnic groups

What is the implication of this?

A

Present in all ethnic groups, but in different proportions

Implication:
KIR epitopes are requisite for survival of population?

25
Q

Compare Bw4 and Bw6 motifs

A

Motif found on HLA-B alleles
Located on alpha helix between residues 77-83

The residues in this location determines whether the allele is Bw4 or Bw6

26
Q

Compare C1 and C2 epitopes

A

Defined by aa at residue 80:
Either Asn or Lys
Can either be one or the other

Thus, mutually exclusive

27
Q

Describe the structure of KIR

A

Ig-like

Two Beta sheets in series

Interface between the two domains that generates the receptor binding site
(different from TCR)

28
Q

Describe physically how KIR interacts with MHC:peptide

A

Interacts at one side of MHC

unlike with TCR, which interacts at the middle

29
Q

Describe NK receptor expression within individuals

What is the significance of this?

A

Within an individual, NK receptor expression is variegated
(possible random?)

Some NK cells express each of:
 • CD158a (KIR-2DL1)
 • CD158b (KIR-2DL2/3)
 • CD158e (KIR-3DL1)
 • KIR-3DL2
 • CD94/NKG2A

The same NK cell can express multiple receptors

Significance:
• Some viruses are sneaky and selectively down regulate MHC eg HIV down regulates HLA-A, HLA-B but not HLA-C or HLA-E
• Having NK cells with different receptor expression means that some NK cells will still be able to detect infection, even though not all MHC is down regulated
NB NK cells expression receptor for HLA-C will still see their ligand and think that the cell is healthy

30
Q

Describe herpes virus HLA down-regulation

A
  1. When HSV infects a cell, is expresses a protein that interferes with TAP
  2. All types of HLA are not loaded with peptide
  3. They are retained in the ER and eventually destroyed
31
Q

Describe clinical significance of Bw4 alleles

A

Associated with better outcomes

HIV protein Nef downregulates HLA-B, but doesn’t touch HLA-C

CD158e+ NK cells recognise HLA-Bw4

Thus, CD158e+ NK cells are really important in HIV infections and equate to a slowed progression to AIDS

32
Q

Describe the clinical consequence of KIR-ligand matching in transplantation

Explain this phenomenon

A

Paper looking at BM transplant for the treatment of leukaemias

Looked through all the transplants and the genetics

Grouped people based on KIR-ligand-match or KIR-ligand-mismatch

Analysed success of transplant

No KIR-ligand incompatibility:
• 15% rejection
• 13% acute Graft vs Host disease
• 75% relapse in AML

KIR-ligand incompatibility:
• 0% rejection
• 0% acute Graft vs Host disease
• 0% relapse in AML

Explanation
• Distinct population of donor derived NK cells are preferentially activated when there is no ligand for them present
Example scenario:
• The donor cells express either CD158a, CD158b or CD158e
(Depending on the receptor, the NK cell recognises different ligands)
• Recipient cells express various ligands that inhibit all the various donor NK cells
• In this patient, there is no NK cell receptor mismatch –> rejection
• A different recipient has cells that express different ligands
• This person doesn’t have an MHC allele that inhibits eg CD158e+ NK cells or CD158a+ NK cells
• Some NK cells activated to mediate lysis and killing
–> no rejection

33
Q

What is Graft vs Host disease?

A

Transplant performed

Graft immune system attacks the recipient of the organ

34
Q

Describe what the following receptors recognise:
• CD158a
• CD158b
• CD158e

A

CD158a: Group 2 HLA-C

CD158b: Group 1 HLA-C

CD158e: HLA-Bw4

35
Q

What is the point of BM transplants for leukaemia?

A

Graft that comes in clears tumours

36
Q

Which FcR do NK cells have?

A

FcγRIII

MIIM30002 - Principles of Immunology (30 decks)

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