55. Natural Born Killers

Question 1

Origin of NK and T cells

Answer 1

• Both arise from common lymphoid progenitor cell

* Both part of the lymphocyte lineage

Question 2

Role of cytotoxic lymphocytes

Answer 2

•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

Question 3

Role of MHC class I : Antigen Presentation

Answer 3

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

Question 4

T cell receptor recognition of MHC

Answer 4

• 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

Question 5

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

Answer 5

• 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

Question 6

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

Answer 6

•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)

Question 7

What are NK cells? and what do they do?

Answer 7

• 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

Question 8

NK cells and infection

Answer 8

•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

Question 9

Recognition of MHC-I by receptors on NK cells

Answer 9

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

Question 10

Function of Killer Ig-like receptors (KIR)

Answer 10

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”

Question 11

Killer Ig-like Receptors (KIR)

Answer 11

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

Question 12

Natural cytotoxicity receptors (NCRs)

Answer 12

• 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

Question 13

Antibody-dependent cell-mediated cytotoxicity (ADCC)

Answer 13

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

Question 14

Why do NK cells kill tumour cells?

Answer 14

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.

Question 15

Mechanisms of lysis – cytotoxic granules

Answer 15

• 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)

Question 16

Proteins in granules of the cytotoxic T cells

Answer 16

• 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

Question 17

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

Answer 17

• 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)