Immunology III: Innate Immunity & Inflammation 2 (Part 4: NK cells and IFNs)

Question 1

Interferons and the antiviral response: What are the 2 major groups? What secretes them? What’s their role?

Answer 1

Group 1 – interferon-alpha (IFN-) and interferon-beta (IFN-)
Secreted by macrophages, dendritic cells, and cells that have detected viruses via PRRs
Role – to “interfere” with viral replication in a wide variety of cells
Receptors for these Group 1 IFNs found on most cells
Group 2 – interferon-gamma (IFN-)
Secreted by Th cells and NK cells
Role – activates macrophages and “pushes” the adaptive immune system to a cell-mediated response (more later)

Question 2

What fashion do type 1 interferons act in? What happens if their response is inadequate?

Answer 2

Type I interferons act in an autocrine and paracrine fashion to provide a rapid, innate protection to viral infection
If Type-1 IFNs and the NK response is inadequate, then we rely on the adaptive immune response

Question 3

How do interferons “interfere” with viral replication inside cells?

Answer 3

1.) Inhibit of protein translation in the presence of viral RNA
2.) Degrading viral mRNA
3.) Inhibition of viral protein assembly

The net result is that type 1 IFNs reduce the ability of infected cells and the virus to synthesize and assemble proteins

Question 4

The Natural Killer (NK) Cell: What is it? How is it activated? What is its role?

Answer 4

A specialized cell that is derived from the lymphoid lineage, but has a relatively non-specific way of detecting cancer cells or virally-infected cells

No highly-specific, unique TCR or BCR

Large lymphocytes that are activated by Type 1 IFNs and IL-12

Kill cells that are infected by viruses

Secrete cytokines that predispose the adaptive immune system to adopt a response that relies on cellular effectors rather than antibodies (more later)

Question 5

The NK Cell: What does it survey the body for? What kind of receptors do they have? What does each type of receptor do?

Answer 5

NK cells survey the body for infected or “stressed”, abnormal cells

NK cells have “activating” and “inhibitory” receptors

NK Activating receptors (NKARs) detect molecules expressed on the membrane of cells that are infected by viruses or have developed into cells that may be malignant

NK Inhibitory receptors (NKIRs) detect molecules that are typically expressed by “normal” cells

Question 6

The NK Cell examples.

Answer 6

NKARs – examples
NKG2D – an NK receptor that detects “strange” MHC-I molecules on cells

These abnormal MHC-I proteins can not present intracellular antigens and are more typically expressed by virally-infected cells or cells with damaged genomes (i.e. cancer cells)

NKIRs - examples
KIR – an NK receptor that detects normal MHC-I molecules on a cell membrane
These MHC-I molecules can present antigens

Question 7

NK cells: rules they live by!! What must they do before activation? What’s the process of killing the cell?

Answer 7

Before NK cells can be activated, they need to be licensed to make sure their NKIRs are functional

This is likely done by dendritic cells – protects the body from indiscriminate NK-killing and tissue damage

Once they are activated and licensed, they travel to areas of damage/inflammation and “survey” the cells

NKIRs “over-rule” NKARs – if a cell expresses mostly normal MHC-I proteins, for example, then the NK cell does not kill it
If there are many abnormal MHC-I proteins, then the NKARs “over-rule” the NKIRs, and the NK cell kills the abnormal cell

Question 8

When NKARs are activated, it kills the cell by:

Answer 8

Receptor-mediated apoptosis via Fas-Fas ligand interaction

Secretion of the proteins perforin and granzyme

Perforin pokes holes in the membrane

Granzyme directly activates the BH3-only apoptotic protein Bid as well as executioner caspase 3