Innate Immunity V

What must dendritic cells do in order to present an antigen?

Mature from their immature form (tissue-resident)

What are the hallmarks of maturation for dendritic cells? Once they are mature where can they migrate to?

1. Expression of CD80/CD86 and CD40

2. Upregulation of MHC II

3. Production of IL-12

4. CCR7 (chemokine receptor)

The lymph nodes

What are two factors that induce maturation of dendritic cells?

1. TLR binding

2. TNF and IL-1beta is produced in response to acute phase cytokines

What does TLR 4 or TLR5 bind to on a dendritic cell? What does it produce?

Bacteria and produces IL-12

What 2 receptors are expressed on a dendritic cell for naive T cells?

1. CD28

2. CD80/86

What 2 receptors are expressed on a naive T cell?

1. MHC II with peptide if presenting

2. TCR

How are TH1 cells produced?

A naive T cell will present an antigen via MHC II to a dendritic cell. With the help of IL-12 a TH1 cell is produced that will be very good at producing IFN-y to fight the infection

What does TLR3 or TLR7 or TLR9 bind to on a dendritic cell? What does it produce?

Virus and produces IL-12

What does Dectin-1 bind to on a dendritic cell? What does it produce? What is dectin-1?

Fungi and produces IL-6 and IL-23. It is a CLR

What does NOD1/2 bind to on a dendritic cell? What does it produce?

Bacteria and produces IL-10

How are TH17 cells produced?

A naive T cell will present an antigen via MHC II to a dendritic cell. With the help of IL-6 and IL-23, TH17 will be produced which in turn will produce IL-17 to fight the infection.

What does TLR2/1 bind to on a dendritic cell? What does it produce?

Helminth (worm) and produces IL-10

How are TH2 cells produced?

A naive T cell will present an antigen via MHC II to a dendritic cell. with the help of IL-10, IL-4, and IL-13 the TH2 cells will be produced and in turn IL-4, IL-5, and IL-13 are secreted.

What happens if you give vitamin A to a dendritic cell?

It will cause retinoic acid (RA) to be produced

What does TLR2/6 bind to on a dendritic cell? What does it produce?

Binds fungi and produces IL-10 and TGF-B

How are TREG cells produced?

A naive T cell will present an antigen via MHC II to a dendritic cell. With the help of IL-10 and TGF-B TREG cells will be produced and in turn will secreted IL-10 and TGF-B.

What is TH17 good at fighting?

Fungi

What are NLRs?

They are nod-like receptors that are intracellular complexes that bind to PAMPs (conserved microbial features) and DAMPs

What can some NLRs assemble into?

Inflammasomes

What do inflammasomes contain?

Proteases

What does the inflammasome do?

It converts precursor form of IL-1B and IL-18 into active inflammation promoting cytokines via caspase-mediated cleavage (acute phase) (once caspase-1 is activated)

What do inflammasomes work in tandem with? Why?

Other PRRs in response to PAMPs and DAMPs to prime the inflammatory response

Describe the structure of NLRs

Have a domain that binds to an antigen or structure of interest. This domain is connected to an enzyme called caspase 1

What are sterile activators?

They are DAMPs that come from your own body

What are two types of sterile activators that are self-derived?

1. ATP

2. Glucose

What are two types of sterile activators that are environment-derived?

1. UV radiation

2. Asbestos

What is a pathogen activator for NLRs that is bacteria derived?

Peptidoglycan fragment

What is a pathogen activator for NLRs that is virus derived?

RNA

What is a pathogen activator for NLRs that is fungi derived?

Hyphae

What is a pathogen activator for NLRs that is protozoa derived?

Hemozoin

What is the NLRP3 inflmmasome expressed by?

1. Monocytes

2. Macrophages

3. Neutrophils

4. Dendritic cells

5. Some lymphocytes

6. Epithelial cells

Describe how a NLRP3 inflammsome is formed and what it does

1. NLRP3 will oligomerize with procaspase 1 and NEK7

2. Once a PAMP is introduced then pro-IL-1B in the cytoplasm is cleaved into the active IL-1B form

3. Inflammation begins

How many human CLRs are there?

15

What do CLRs recognize?

Carbohydrate components (glucans) on fungal cell walls

What does binding of CLRs to carbohydrate components on cell walls trigger?

Intracellular signalling and phagocytosis

Describe how Dectin-1 can turn on multiple transcription factors

1. Dectin-1 will bind to carbohydrate components on a fungal cell wall

2. ITAM will be phosphorylated and acts as a docking site for tyrosine kinase

3. Tyrosine kinase will phosphorylate PLC(delta) causing it to become activated

4. PLC(delta) activation will then cause activation of multiple transcription factors

What are the four transcription factors that are eventually produced from CLR?

1. IRF5

2. NF-kB

3. AP-1

4. NFAT

How is IRF5 produced? What does it do?

Activation of PLC(delta) will transcribe IRF5 and this protein will go to the nucleus. Can then signal type I IFNS

What pathway produces NF-kB? What does it do?

After the activation of PLC(delta) the NF-kB activation pathway begins. It is responsible for production of type I IFNs and chemokine and antimicrobials

What pathway produces AP-1? What does it do?

After the activation of PLC(delta) the MAP kinase pathway begins. It produces cytokines, chemokines and antimicrobials

How is NFAT produced? What does it do?

Can occur during T cell activation. In addition after PLC(delta) is activated it produces calcium that will bind to calmodulin that will produce NFAT. It produces cytokines, chemokine and antimicrobial

How is CLR and TLT signalling similar?

Through distal events as they both activate NF-kB, IRFs, and AP-1

Can TLR and CLR signalling occur in the same cell? If yes, what is a benefit to this?

Yes and they can combine to enhance the production of inflammation-promoting cytokines

What is the function of neutrophils?

1. Phagocytosis

2. Have reactive oxygen and nitrogen species

3. Have antimicrobial peptides

What do macrophages do?

1. Phagocytosis

2. Inflammatory mediators

3. Antigen presentation

4. Reactive O and N species

5. Cytokines

6. Complement proteins

What do dendritic cells do?

1. Antigen presentation

2. Costimulatory signals

3. Reactive O species

4. Interferon

5. Cytokines

What do NK cells do? Where are they found?

1. Lysis of viral infected cells

2. Interferon

3. Macrophage activation

In circulation and tissues

What do T cells do?

They will clear any virally infected cells that the NK cells couldn’t

What immune cell is the first line of defence against viral infection? Why?

NK cells because of their rapid activation by type I IFNs and by IL-12 produced by dendritic cells. Can start killing the virus while the T cells become activated.

Are NK cells important for virus-specific CTL induction (part of adaptive immunity)? If yes, why?

Yes they are because of their production of CTL-promoting IFN-y

How are NK and ILCs different?

NK cells are the circulatory form

What are NK cells?

They are non-specific cytotoxic effector cells that provide an early defence against viruses and cancer. Can also kill fungi and bacteria.

What percentage of NK cells made up the peripheral blood lymphocytes?

5-10%

What do NK cells arise from? Are they more closely related to T or B cells?

T/ILC progenitor downstream of the common lymphocyte progenitor. T cells

What are the four functions of NK cells?

1. Produce IFN-y and respond to Type I IFN

2. Induce target cell death through receptor-ligand signalling and release of toxic products (ie perforin/granzyme)

3. Respond to antibodies bound to target cells by inducing antibody-dependent cellular cytotoxicity (ADCC)

4. NK cell function is regulated by MHC receptors

What is perforin? What is it analogous to? Describe how it works

It is a pore forming protein that is analogous to C9 complement. Perforin is released from a granule and will form a pore in a bacterial cell. Granzyme can then get through and initiate apoptosis

What is ADCC?

It is when a target cell is coated with antibodies and Fc receptors will bind to it and activate NK cells that will degranulate and kill it

What are NK cells inhibited by?

MHC receptors. Therefore, they kill cells deficient with MHC receptors.

Describe how NK cells are activated?

1. Have infected cell

2. Type I IFN will eventually be activated and will bind to type I IFN receptor

3. NK cells are now activated and will proliferate and differentiate into cytotoxic effector cells

4. Can now dump granules and kill the cells by inducing apoptosis