55. Natural Born Killers Flashcards Preview

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Flashcards in 55. Natural Born Killers Deck (17)
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1
Q

Origin of NK and T cells

A
  • Both arise from common lymphoid progenitor cell

* Both part of the lymphocyte lineage

2
Q

Role of cytotoxic lymphocytes

A

•We need cytotoxic cells as a means to destroy

  • cells infected with bacteria, viruses or parasites
  • Tumour cells

•This requires a cell-surface mechanism to display what is going on within a cell

3
Q

Role of MHC class I : Antigen Presentation

A

MHC class I proteins are found at the cell surface and form a structure that holds antigenic peptides for surveillance by T cells

MHC-I = recognised by CD8+ cytotoxic T cells

4
Q

T cell receptor recognition of MHC

A
  • MHC-I and MHC-II play a central role in the ability of the immune system to distinguish self from non-self
  • TCR recognise two things
    • MHC protein itself (hence compatibility…)
    • Antigenic peptide presented by MHC protein
  • TCR recognises both the MHC protein and the peptide antigen being presented by it
  • Binds with a diagonal footprint that cuts across both alpha helices with the peptide in between
5
Q

Distant binding sites allow CD8 and TCR to bind MHC-I at the same time. Expand.

A
  • CD8 acts as a co-receptor for MHC-I, and is required for the T cell to make an effective response
  • TCR binds to the α1α2 domains
  • CD8 binds to the support domains (α3 and β2m)
  • Similar situation for CD4 and MHC-II
6
Q

How do adenovirus, HSV, HCMV, and HIV subvert MHC upregulation?

A

•Inhibit MHC-I transcription (adenovirus)
•Block TAP activity (HSV)
Retain MHC-I in endoplasmic reticulum (adenovirus, HCMV)
•Target MHC-I for disposal from ER (HCMV)
•Downregulate MHC-I from cell surface (HIV)

7
Q

What are NK cells? and what do they do?

A
  • 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+

=> Cytotoxic functions and cytokine secretion

8
Q

NK cells and infection

A

•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

  • 4 children, EBV-driven lymphoproliferative disorder, severe respiratory illnesses
9
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

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

10
Q

Function of Killer Ig-like receptors (KIR)

A

When KIR recognise MHC-I they inhibit NK cells from releasing lytic granules

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”

11
Q

Killer Ig-like Receptors (KIR)

A

Inhibitory KIR bind to the same face of MHC-I as the T cell receptor

recognise subsets of MHC-I alleles

KIR are also polymorphic, as well as being polymorphic individual KIR genes vary in their presence between individuals

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

12
Q

Natural cytotoxicity receptors (NCRs)

A
  • These provide activating signals to NK cells, but are not well characterised
  • NCR 1 binds viral hemagglutinin
  • NCR2 – binds a ligand that is expressed on tumor cells and upregulated by viral infection

•Ligand for NCR3 is a stress induced
protein

13
Q

Antibody-dependent cell-mediated cytotoxicity (ADCC)

A

Antibody binds antigens on the surface of target cells

Fc receptors on NK cells recognise bound antibody

Cross-linking of Fc receptors signals the NK cell to kill the target cell

Target cell dies by apoptsis

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.

15
Q

Mechanisms of lysis – cytotoxic granules

A
  • NK cells and T cells carry granules filled with cytotoxic proteins
  • Release cytotoxic granules at site of contact with target cell
  • (must be directed in order to avoid damaging innocent bystander cells)
16
Q

Proteins in granules of the cytotoxic T cells

A
  • PERFORIN - 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
  • GRANULYSIN - Has antimicrobial actions and can induce apoptosis
17
Q

CD8 cells can trigger apoptosis of target through Fas/FasL interaction. Expand.

A
  • This process does not depend on cytotoxic granules
  • Fas ligand (FasL) on T cells engages Fas on target cells to trigger apoptotic pathway
  • Fas/FasL triggered apoptosis is used to dispose of unwanted lymphocytes
  • Loss of Fas can result in autoimmune lymphoproliferative syndrome (ALPS)

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