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Immunity and infection > Natural Killer cells and gamma/delta T cells > Flashcards

Natural Killer cells and gamma/delta T cells Flashcards

1
Q

Describe the origins of NK cells

A

Natural killer cells are a subset of
Innate Lymphoid Cells

Transcription factors (e.g. T-bet, GATA3 and RORgt) determine phenotypic differences between ILC subsets

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2
Q

What are NK cells?

A

A group of lymphocytes that have the intrinsic ability to recognize and destroy some virally
infected cells and some tumor cells.

Classical NK cells are large granular lymphocytes that are not T or B cells

Do not express T Cell Receptor (CD3) or B
cell receptor

Do express the cell surface marker CD56

CD3-CD56+

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3
Q

Q. What markers would one normally use to distinguish T cells from NK cells?

A

A. CD16 and CD56 are used to distinguish NK cells. CD3 is characteristic of T cells.

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4
Q

What do NK cells do?

A

NK cells are the lymphoid effectors of
cytotoxicity

Cytokine secretion

NK cells can also mediate antibody dependent cell-mediated cytotoxicity (ADCC)

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5
Q

Describe NK cell subsets

A

The best characterised subsets are defined by
their expression level CD56

Around 10% of NK cells are CD56bright –
predominantly found in secondary lymphoid
organs, greater cytokine production

The majority of circulating human NK cells have
low CD56 expression – predominantly found in
blood, highly cytotoxic

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6
Q

Describe the roles of the cytokines released by NK cells

A

(IFN-y):
- activation, growth and differentiation of T, B, NK cells and macrophages
-promotes Th1 differentiation
-enhances MHC expression on APC

(TNF-a):
- Inflammatory mediator
- regulates growth and differentation of a wide variety of cells
- selectively cytotoxic for many transformed cells

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7
Q

Describe the actions of protein in granules in NK cells

A

Perforin - is a monomeric pore-forming protein. inactive within the granules, but undergoes a conformational activation, which is Ca2+-dependent. Aids in delivering contents of granules into the cytoplasm of target cell.

Granzymes - serine proteases, which activate apoptosis once in the cytoplasm of the target cell. granzyme B cleaves pro-caspases 3, 7, and 8, triggering apoptosis in the target cell. granzyme A triggers apoptosis via a caspase-independent pathway

Granulysin - has antimicrobial actions and can induce apoptosis.

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8
Q

Role of NK Cells in cancer and infection

A

Role in cancer
* Medium and high cytolytic function was associated with reduced cancer risk; low cytolytic function was associated with increased cancer risk

Role in infection
* Low NK cell activity correlates with severe disseminating herpesvirus infections
* NK cell deficiency
– 13 year old girl, overwhelming chickenpox, later developed life- threatening primary HCMV infection, severe HSV

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9
Q

What determines NK cells decision to kill?

A

NK cells can also recognize antibody on target
cells using Fc receptors

NK cells express inhibitory receptors that bind to MHC class I molecules. When they encounter a target cell that is not expressing MHC class I, this inhibitory signal is lost and tonic activating signals cause the NK cell to degranulate

The balance of inhibitory and activating
signals determines whether an NK is activatedor produce cytokines in response to the target cell.

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10
Q

Describe Antibody-dependent cell-mediated
cytotoxicity (ADCC)

A

The Fc receptor CD16 (FcgRIII) is expressed by all CD56low NK cells, but not by CD56hi cells. CD16 binds antibody bound to target cells, activating the NK cell so that it degranulates, mediating antibody dependent cell-mediated

NK cell-mediated ADCC requires both an adaptive immune stimulus (cells coated with antibody) and an innate immune effector mechanism (NK cells) and is thus an example of cross-talk between the innate and adaptive immune systems.
cytotoxicity (ADCC)

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11
Q

Describe the inhibitory and activating NK receptors

A

NK cells are controlled by a balance of signals from activating and inhibitory receptors

Inhibitory receptors contain an immunoreceptor tyrosine inhibitory motif (ITIM) in their long cytoplasmic tails. These recruit inhibitory phosphatases, which disrupt phosphorylation of activating receptors and
intracellular signaling molecules, and prevent NK cell activation.

Activating receptors signal through ITAMs. (immunoreceptor tyrosine-based activation motif). Short cytoplasmic tail, requires adaptor protein This allows them to phosphorylate and recruit tyrosine kinases

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12
Q

Recognition of MHC-I by receptors on NK cells

A

Killer Ig-like receptors (KIR) are innate immune receptors that regulate the activity of Natural Killer cells

Leukocyte Ig-like receptors (LILR) are innate immune receptors that regulate the functions of NK cells and antigen presenting cells

KIR and LILR are encoded in a gene complex (the leukocyte receptor complex or LRC) on chromosome 19

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13
Q

Function of Killer Ig-like receptors (KIR)

A

The killer immunoglobulin-like receptors, or KIRs, are members of the immunoglobulin superfamily. They are present on the majority of CD56 low NKcells. Almost none of the CD56hi NK cells express KIRs

KIR are also polymorphic. Individual KIR
genes vary in their presence between
individuals

Different MHC-I/KIR combinations show disease associations e.g. in HIV infection

  • When KIR recognise MHC-I they inhibit NK cells from releasing lytic granules
  • Inhibitory KIR bind to the same face of MHC-I as the T cell receptor
  • recognise subsets of MHC-I alleles
  • Some viruses down-regulate MHC-I as a means to evade cytotoxic T cells, loss of MHC-I is also a common feature of tumour cells
  • If a target cell does not express MHC-I then there is no KIR inhibition, lytic granules will be released to lyse the target
  • Known as “missing self”
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14
Q

Why do NK cells kill tumour cells?

A

Similar to many pathogens, tumor cells can escape the adaptive immune system, by downregulating the expression of MHC class I.

This makes them more susceptible to NK cells.

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15
Q

Complexity of KIR receptors (1) nomenclature

A
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16
Q

Training NK cells – license to kill

A

NK cells need ligation of the inhibitory receptors to ‘license them’ to become mature.

This supposes that the inhibitory receptors play 2 opposing roles dependent on the stage of NK
maturation: i) to license the cell and ii) to stop cytotoxicity

Now also proposed that the level of responsiveness may alter during disease and this sets the threshold of NK actiation

17
Q

Inhibitory and activating receptors – exist as heterodimers (c-type lectin-like)

List them

A

CD94/NKG2A : Inhibitory
CD94/NKG2C: Activating
CD94/NKG2E Activating

Recognize HLA-E on target cell

18
Q

The lectin-like receptor CD94 recognizes
HLA-E

Describe this

A

The ligand for both CD94- NKG2A and CD94-NKG2C is HLA-E, although the inhibitory CD94-NKG2A has greater affinity for HLA-E than its
activating counterpart.

The HLA-E gene locus encodes an MHC class I-like molecule. These are sometimes called non-classical class I molecules, or class Ib molecules, to distinguish them from the classical MHC molecules that present antigen to CTLs. The function of HLA-E is to present peptides from other MHC class I molecules.

Thus NK cells are able to detect a reduction in
the overall synthesis of MHC I.

19
Q

Describe Leukocyte Ig-Like Receptors (LILR)

A
  • Encoded adjacent to KIR in the leukocyte receptor complex (LRC)
  • LILRB have inhibitory motifs, LILRA short tail and associate with adaptor proteins
  • Powerful immune inhibitor

LILRB1 interacts with a broad spectrum of MHC class I molecules. LILRB1 is expressed by a proportion of NK cells

Thus LILRB1, like CD94-NKG2A, allows NK cells to detect target cells that are expressing low levels of any MHC class I molecule.

LILRB1 recognizes both classical and non-classical MHC class I molecules, but it has a particularly high affinity for the non-classical molecule HLA-G, whose expression is restricted to extravillous trophoblast cells in the placenta.

Interaction of LILRB1 with HLA-G inhibits NK cell
cytotoxicity more strongly than that with other class I molecules.

20
Q

Describe NKG2D and its ligands

A
  • Expressed on gd T cells, CD8+ ab T
    cells and macrophages
  • Associates with DAP10 for signalling
  • Binds to MHC-I –like proteins MICA, MICB,
    ULBPs
  • an activating receptor expressed by all NK cells
  • Expression of these molecules is upregulated by a variety of cellular stresses including heat shock, oxidative stress, proliferation and viral infection. Thus, NKG2D allows NK cells to recognize cells that are stressed, including virally infected and cancerous cells.

NKG2D does not associate with CD94, instead
forming a disulphide-linked homodimer

21
Q

MHC recognition by NK cell receptors

A

Inhibitory receptors and missing self
– KIR and classical MHC
– LILR: classical and non-classical MHC (particularly HLA-G)
– NKG2A, B and C: non-classical MHC

Activating receptors and induced self
- NKG2D: MICA, MICB, ULBPs

22
Q

Describe Natural cytotoxicity receptors (NCRs)

A
  • NCRs – NCR1,NCR2 and NCR3 provide activating signals to NK cells
  • NCR 1 ligands include viral hemagglutinin
  • NCR2 – binds a ligand expressed on tumor cells and upregulated by viral (HIV) infection
  • Ligand for NKp30/NCR3 is BAT3 a stress induced protein
23
Q

Compare Natural killer cells and Cytotoxic T cells

A
24
Q

Describe the Immune evasion of CMV and cancer

A

CMV produces UL16 which binds NKG2D ligands and retains them in the cytoplasm. Prevents NK recognition and also co-recognition of CD8 T cells

Cancer cell produces soluble MIC as a decoy

25
Q

Describe the Immune evasion of HLA-G

A
  • HLA-G would only normally be expressed by trophoblast during pregnancy, but is expressed
    by many tumours and may be upregulated in HIV infection
  • HLA-G is highest affinity ligand for the inhibitory receptor LILRB1
  • LILRB1 is expressed on B cells, NK cells, T cells and antigen presenting cells and can inhibit the
    functions of each
26
Q

Other innate lymphocytes
NKT cells

A

*NKT cells have T markers and also some NK cell markers: they express CD3 and have a unique ab TCR
*Express some NK inhibitory and activation receptors
*Relevant in bacterial and viral infection
*Can kill tumour target cells in vitro
*In response to antigen they are capable of producing large amounts of IFNg and IL-4. NKT cells are therefore thought to act as an interface
between the innate and adaptive systems by initiating T cell responses to non-peptide antigens.
*NKT cells are thought to recognize glycolipid antigens presented by CD1d molecules but not conventional MHC molecules
*a-galactoceramide and DC vaccination

27
Q

Describe CD1 in the context of NKT cells

A
  • Encoded outside MHC
  • Specialised binding groove presents glycolipids or
    phospholipids
  • many lipids (and glycolipids) differ between microbes and mammals
  • Recognised by specialised subsets of TCR (Va24/Vb11 )
28
Q

Describe Gamma delta (gd) T cells

A
  • Unconventional T cells
  • Mechanism of selection largely unknown
  • Generally enriched in mucosal and epithelial
    tissues
  • MHC independent
  • TCR and NK-receptor (NKG2D) activation
    *Minor population of T cells in peripheral blood
29
Q

Describe TCR gd

A
  • d gene found serendipitously
  • Located within the alpha locus
  • Then discovered g
  • Limited V gene segments in both g and d locus
  • d has numerous D gene segments
  • Junctional diversity leads to potentially many
    CDR3 sequences
  • Limited pairing between g and d chains.
  • Animal models suggest that the TCR is responsible for the localization of the cell to tissues
30
Q

Describe Vd1 (DOT) T cells

A
  • Usually 10-30% of the gd T cells in the blood
  • More highly represented in tissue
  • Use TCR and NK receptors to identify tumour
    targets.
  • Recognise CD1d/lipid complexes and NKG2D
    ligands
  • MHC recognition (allo)
  • Role in homeostasis and stress surveillance
31
Q

Describe Vd2 T cells

A
  • Usually about 4% on normal PBLs but can
    expand rapidly to 60%+ in infections
  • Vg9Vd2 but also termed Vg2Vd2 (Semi-
    invariant TCR) In humans and NHP.
  • Recognise small phosphoantigens e.g. Iso-
    pentenyl pyrophosphate (IPP- endogenous)
    and (E)-4-hydroxy-3-methyl-but-2-enyl-
    pyrophosphate (HMBPP-bacterial) 10000x
    better than IPP
  • Thought to be presented by Butyrophilin3A1
  • Can also recognise NKG2D ligands
32
Q

Describe Butyrophilin

A

Part of the B7 receptor family-like proteins
Two extracellular Ig-like domains BTN3A1, A2 and A3.
BTN3A1 is essential for pAg recognition but the others play a lesser role.
Still being determined.

Does not appear to present pAg in the usual, MHC-like way BTN3A1 has an intracellular region 30.2 which binds pAg. This binding changes the conformation of the extracellular portion of
BTN3A1 which renders the molecule recognisable to Vg9Vd2 cells.
Role of accessory molecules?
Sensor for intracellular infection and cancer.

33
Q

Effector functions of gd T cells

A
  • Cytokine production: Th1-like: gIFN and TNFa
    or Th17-like IL-17
  • Cytotoxicity against infected (viral and bacterial) or transformed cells
  • Degranulate like NK cells, perforin, serine esterases, granulysin.
  • Thought to be a rapid response cell in immunosurveillance
    *gd T cells have been shown to be endocytic and can present peptide in the context of MHC.
  • The infiltration of gd T cells into tumour has
    the highest positive prognostic value
34
Q

gd T cell therapy

A
  • Aminobisphosphonates:
    Pamidronate, Alendronate and Zoledronic acid.
  • Blocks mevalonate pathway and causes accumulation of IPP which binds 30.2 region
    of BTN3A1
  • Both approaches used, expand Vg9Vd2 cells.
    Limited success in vivo, rapid sequestration of
    the drug by bone
  • Expansion of DOT cells, secret recipe! gd
    Therapeutics
  • Safe but not yet optimised

Immunity and infection (29 decks)

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