L21 Cytotoxic cells & anti-viral responses

Question 1

What does an interferon do?

Answer 1

Interferes with viral infection? It’s a large family of cytokines (type 1, 2 and 3)

• Type 1 - interferon α and β = KEY antiviral cytokines.
• Type 2 - interferon γ important for Th1 driven immunity

Question 2

What is ISG?

Answer 2

Interferon stimulated gene; gene whose expression is stimulated by interferons. Viruses trigger the type 1 interferon system –> transcription of 100s of ISGs. ISGs have antiviral functions, interfering with all steps of viral life cycle.

Question 3

Examples of what ISGs do?

Answer 3

Classic ISGs include MX1. Potent antiviral activity. Inhibit viral protein synthesis, degrade viral RNA through RNase enzymes, inhibition of viral gene expression and virion assembly. Upregulate MHC1, increases p53 activity.

Question 4

What is PKR - protein kinase R?

Answer 4

Protects against viral infections. Infected cell produces interferons, interferons activate PKR, phosphorylation of translation factor elF2α - which is required for most forms of translation initiation. When phosphorylated it forms an inactive complex which blocks translation and protein synthesis.

Question 5

Can viruses fight IFNs?

Answer 5

YES, they have mechanisms to turn IFN cascade off.

Question 6

What happens when there is dysregulation of innate intracellular DNA sensing? What does STING mean?

Answer 6

failure leads to auto-inflammatory and auto-immune disease e.g. SLE
STING - stimulator of interferon genes. Key role in stimulating interferon production

Question 7

LO1 - how does the innate immune system respond to virus infection?

Answer 7

Recognition of viruses via PAMPs by PRRs.

Interferons made cause expression of antiviral genes that help get rid of virus targeting all stages of life cycle.

Question 8

LO2 - How does the adaptive immune response respond to viral infection?

Answer 8

Intracellular viral antigens prime CD8s. If extracellular virus then prime CD4. Cross presentation can cause exogenous to prime CD8 and endogenous CD4.
MHCI induces T cell proliferation and activation, APC stimulates naive T cells, T cell proliferates with aid of IL-2. It differentiates and then active effector T cell kills virally infected target cells. Engagement of peptide loaded MHCI induces proliferation of peptide specific CTLs. Vriuses can interfere with MHCI. E.g. low MHCI - CTLs cant see it.

Question 9

LO3 - How do NK cells work in antiviral response and in innate clearing of infected cells?

Answer 9

NK cells are able to kill target cells that have lost expression of MHCI i.e. missing self. If they have MHCI they don’t kill. Release granules that trigger apoptosis.

Question 10

LO4 - Adaptive immune responses. How do neutralising abs and direct killing of virus work? How do Non-neutralising abs and indirect killing by ADCC work?

Answer 10

Directly neutralising abs MOA:
	• Block virus/receptor interaction
	• Block endocytosis
	• Block release into cytoplasm
Aggregate virus

Indirectly neutralising abs – ADCC ab-dependent cellular cytotoxicity
• Abs bound to virus can: induce classic complement cascade
Bind to FCγRIII (CD16) receptors on NK cells – activation

Question 11

What happens when ADCC goes wrong?

Answer 11

You get Ab dependent enhancement of infection (ADEI). Non-neutralising antiviral proteins facilitate virus entry into host cells, leading to increased infectivity in the cells. After first infection abs produced but they won’t be neutralising for second round of infection when its mutated. In 2nd infection Fc domain of neutralising abs bind to Fc receptor on cells e.g. NK cells and loads up the antigen binding regions on the other end of the ab and through this gets access to the cell. e.g. in Dengue

Question 12

So what are the key mechanisms of anti-viral immunity?

Answer 12

cytotoxic CD8 T cells
NK cells
ADCC