9/18 Natural Killer Cells

Agenda 1: Natural Killer Cells

What is the category of a NK cell?

• innate lymphoid cell

  • lymphoid lineage (like T and B cells) but with innate functions

Agenda 1: Natural Killer Cells

What are the characteristics of a NK cell?

• innate lymphoid cell

• lacks an antigen receptor

• tissue-resident and circulating

• functionally analogous to CD8+ T cells

• participate in type 1 (Th1) immune responses (transformed cells like viruses and cancer)

Agenda 1.1: Natural Killer Cells’ Purpose

How are NK cells activated? And how are they a bit more advantageous compared to T cell activation?

• dendritic cells and macrophages produce cytokines that “sensitize” NK cells, making them more active and effective killers

  • since they are cytokine-mediated, this makes them much faster than having to activate a T cell

Agenda 1.1: Natural Killer Cells’ Purpose

What do NK cells do? What are they important for?

• directly kill stressed, infected, and/or transformed cells (generally viruses or cancer)

• important for containment of threat while adaptive response matures

Agenda 1.2: Natural Killer Cells’ Activation

How are NK cells activated by the target cells?

• there is no antigen receptor sooo

• there is a collection of activating and inhibitory receptors on the NK cells

• a balance between activating and inhibitory receptors tell the NK cells whether they should kill that target cell or not

  • collection expression profile is different between NK cells within an individual

Agenda 1.2: Natural Killer Cells’ Activation

What signals are needed to activate a NK cell from a dendritic cell?

• Requires 3 signals just like T cells

  • signal 1: activating receptors (various)

  • signal 2: costimulatory molecules (various)

  • signal 3: cytokines

Agenda 1.2: Natural Killer Cells’ Activation

How can activating receptors be activated?

• activating receptors

  • recognize ligands upregulated by stressed or infected cells (PRR signaling, DNA damage, metabolic stress, heat shock, increased proliferation, etc.)

  • TRAIL binds to death receptors on target cells

  • induce cytokine production and cytotoxicity

Agenda 1.2: Natural Killer Cells’ Activation

How can inhibitory receptors be activated?

• inhibitory receptors

  • recognize ligands highly expressed by most healthy self cells

  • these ligands can be downregulated in infected/stressed cells

  • MHC-I should be expressed by all nucleated cells

Agenda 1.2: Natural Killer Cells’ Activation

What does CD8+ T cells do? And what is a downside of their function? How can NK cells help with that?

• CD8+ T cells hunt dangerous invaders by recognizing the antigen bound to the MHC-I of infectors

• however, a lot of viruses/tumor cells may downregulate MHC-I to evade immune responses

• sooo, if MHC-I is missing (which it has no normal excuse to be gone), then NK cell would take that as it is a foreign/transformed cell, and would kill

Agenda 1.2: Natural Killer Cells’ Activation

Referring to the last question, if there is no MHC-I, can the NK cell kill it immediately? Why is this crucial?

• no, it must have activating receptors activated in order to kill a cell without MHC-I

• this is important because our red blood cells do not express MHC-Is, and since healthy RBCs won’t have activating receptors, the signal to kill won’t be activated

Agenda 1.3: Natural Killer Cells’ Effector Functions

What are the effector functions of an NK cell?

• contain cytotoxic granules (granzymes and perforin) that kill targets

• TRAIL-TNFR signaling triggers apoptosis in target cells

• Fc receptor binding → antibody-dependent cellular cytotoxicity (ADCC)

• produce cytokines to further activate macrophages and dendritic cells

Agenda 1.3: Natural Killer Cells’ Effector Functions

What is ADCC a way of?

• ADCC is a way for NK cells to interact with the adaptive immune system

  • so, this method requires activated B cells

  • antibodies produced by the B cells bind to TC, and then the NK receptors called CD16 bind to the Fc regions on the antibodies. with enough binding (cross-linking), it sends a big signal to the NK cell to kill this TC (the NK cell activated other innate cells that could’ve triggered apoptosis)

Agenda 1.4: Natural Killer Cells Memory

What are the skills of a memory NK cell?

• enhanced cytotoxicity, cytokine production, and secondary expansion

Agenda 1.4: Natural Killer Cells Memory

What is the mechanism of NK cell memory?

• not fully understood

• some activating receptors bind ligands expressed by common viruses (especially HCMV)

• infection with those viruses causes expansion and memory formation of NK cells expressing those activating receptors

  • each NK cell have their own signaling activating receptors. so for example, if the infection activates receptors 1 and 3, then proliferation would lead to an increase in NK cells with receptors 1 and 3

• dependent on cytokine signals

Review Revised antiviral response

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