6. natural killer cells

what kinds of pathogens does the acute inflammatory response target?

extracellular bacteria & fungi

what types of pro-inflammatory molecules induce vascular changes? (acute inflammatory response)

• substance H

• histamine

• prostaglandins

what types of pro-inflammatory molecules are involved in cell recruitment? (acute inflammatory response)

chemokines (MCP-1; IL-8)

what types of pro-inflammatory molecules alter expression of endothelial adhesion molecules? (acute inflammatory response)

• tumor necrosis factor α (TNF)

• interleukin-1 (IL-1)

what are examples of type I interferons?

• IFN-α

• IFN-β

• (IFN-λ)

what is an example of a type II interferon?

IFN-γ

what cells produce type I interferons?

virally-infected cells (TLR signaling)

effects of type I interferons

1. induce anti-viral state in neighboring cells

2. activate NK cells

3. promote CD8+ T cells (CTLs)

what cells produce type II interferons?

• NK cells

• CD4+ (T_H1) cells

• CD8+ T cells (CTLs)

natural killer cells belong to what lineage?

lymphoid lineage

**note: NK cells are innate lymphoid cells (ILC1)

where do natural killer cells develop?

in bone marrow

what do NK cell granules contain?

perforin & granzyme

perforin

punches holes in target cell membrane

granzyme

activates caspases (enters through holes in cell membrane created by perforin)

caspases

induce apoptosis

are NK cells phagocytic?

NO!

what are the physiologic roles of NK cells?

• defense against infection by viruses and some intracellular microbes

  • first line of cellular defense against viral infections

• defense against tumors

• destroy virus-infected & tumor cells without prior antigenic stimulation

why are NK cells important during viral infection?

they slow viral replication to allow time for CD8+ T cells to arrive

what are the effector functions of NK cells?

1. cytotoxicity

   • kill infected or tumor cells

   • kill antibody-coated cells

2. produce high levels of IFN-γ

why are major histocompatability complex (MHC) class I molecules important for NK cells?

NK cells are looking for MHC class I molecules to determine which cells are “self”

mechanism of direct NK cell-mediated cytotoxicity

• NK cell recognizes:

  • MHC class I negative cells (tumor cells & some virus-infected cells)

  • cell-surface protein on virus-infected cells

• releases granule contents — perforin & granzyme

• induce cell apoptosis

what is the benefit of using apoptosis to kill cells?

does not induce inflammation

how do NK cell receptors determine whether or not to kill a cell?

• normal cells express a certain level of MHC class 1 → engage inhibitory receptors

• inhibitory receptors override activating receptors

• if activating receptor is engaged:

  • + inhibitory receptor also engaged → NK cell not activated → no cell killing

  • inhibitory receptor not engaged → NK cell activated → kill cell

features of NK cell-mediated cytotoxicity

• no priming

• no antigenic specificity; broad range of action

• (potential) memory?

• no MHC restriction

• response amplified by NK cell-activating cytokines

IL-15

cytokine important for the growth and maturation of NK cells

NK cell activating cytokines

• IFN-α

• IFN-β

• IL-12

mechanism of antibody-dependent cell-mediated cytotoxicity

1. target cell coated in antibodies

2. NK cells recognize Fc portion of antibodies using CD16 receptor (type of Fc receptor)

3. release perforin & granzyme on target cell

production of IFN-γ

activated macrophage with phagocytosed microbes produces IL-12 → IL-12 activates NK cell → NK cell produces IFN-γ → IFN-γ further activates macrophages → killing of phagocytosed microbes within macrophages

effector mechanisms of NK cells

1. direct NK cell-mediated cytotoxicity

2. antibody-dependent cell-mediated cytotoxicity

3. produce IFN-γ → killing of phagocytosed microbes within macrophages

**note: NK cells do not directly kill extracellular/intracellular microbes