Cytoxic T cells & NK Cells (1/10)

Question 1

What are the similarities and differences between NK cells and killer T cells?

Answer 1

Question 2

What happens if you have too many cytoxic T cells? Too few?

Answer 2

Too many/too active: autoimmune, hypersensitivity reactions, graft v host disease, transplant rejection

Too few: immunodeficiency syndromes with decreased NK function

Question 3

What makes cytoxic T cells so dangerous?

Answer 3

Cytotoxicity: granzyme/perforin pathway, death receptor pathway (Fas/Fas ligand, TNF-related apoptosis-inducing ligand)

Immune modulation: production of inflammatory cytokines (IFN-gamma, TNF), chemokine secretion, immunomodulatory cytokines (IL-10, GM-CSF)

Question 4

How does the T cell kill?

Answer 4

Activates an endogenous apoptosis program in the target cell

LFA1 (on T cell) and ICAM1 (on target) recognize one another and make a tight seal

TCR and MHC-1 bind and tell the cell if it’s a good match

Porphorin makes a pore → granzymes diffuse into the target and activate the caspase cascade & apoptosis program as a result

FasL on T cell binds Fas on target cell which also activates caspase cascade and apoptosis

Question 5

How do you get rid of the T cells once there is no more virus?

Answer 5

Activated T cell expresses Fas & it can undergo apoptosis

This terminates the immune response

It’s interesting because Fas is same pathway that induces apoptosis on target cells

Note that tumor cells are particularly susceptible the this method of killing

TRAIL (?)

Question 6

• How are T cells activated? Which signals are required?

Answer 6

Dendridic cells present antigen in lymph node/spleen to naïve T cells that have never seen an antigen. Then they decide if it’s the right fit

2 signals are required (safety measure)
• MHC class I/TCR
• CD80/86 on dendridic cell and CD28 on T cell

Question 7

• What else can dendridic cells activate?

Answer 7

CD4 positive (helper T cells) which help the CD8/killer T cells and the B cells

Question 8

• How do DC get the liscence to activate CD8? 2 steps

Answer 8

DC cell shows piece of virus to T cell → activates a CD4+ helper cell which has a lower threshold for activation

CD4 with CD40L activates the CD40 R of the dendridic cell, making the DC more potent

Now the DC is more potent and can turn on the CD8 positive T cell

Question 9

• If there is no liscencing, what happens?

Answer 9

There is no costimulatory signal

Question 10

How do viruses hide from cytoxic CD8 T cells?

Answer 10

Latency: having fewer copies of virus around so fewer are detected i.e. herpes, HIV

Antigenic variation: rapid mutation/tumor markers

Infection of immune privileged sites i.e. the brain

Production of homologs of Bcl-2, the anti-apoptotic molecule

Interfere with the processing/presentation of the MHC I on their surface

Question 11

What is the difference between direct presentation and indirect presentation?

Answer 11

MHC I present peptides from pathogen that have been processed in the ER, loaded, and presented on cell surface

Cross presentation happens only in a specific type of DC

Pieces of dead pathogen are floating extracellularly & would normally be presented on MHC II via endocytosis/MHC II loading

But Class II can only be seen by CD4 helper T cells, which don’t have cytotoxic potential

Instead of getting loaded on to class II, it releases its antigens into the cytoplasm so it can go to the proteasome & get loaded onto MHC I

Question 12

• What if a virus directly infects and shuts down the antigen presenting cell?

Answer 12

(usually suts down MHC I presentation pathway, though not all at once)

Cross-presentation pathways can take over

Question 13

Why don’t DC undergo apoptosis when they present viral particles on their surface?

Answer 13

They don’t have the machinery downstream to undergo apoptosis (even though they express Fas on their surface)

Question 14

• What are NK cells? What receptors do they have?

Answer 14

o Killer cells of innate immunity

o Germline encoded receptors that have many alleleic variants:

o CD56 = adhesion molecule

o CD16 = receptor for Fc gamma (part of IgG) which binds IgG and stimulates antibody dependent cytotoxicity

o KIR = recognizes MHC class I molecules

Question 15

Where can NK cells be found?

Answer 15

Peripheral blood

Secondary lymphoid organs: bone marrow, spleen, activated lymph nodes

Peripheral tissue: liver, lung, and decidual lining of uterus

Question 16

• What are the 2 subsets of human NK cells? Slide 22

Answer 16

CD56 bright: make lots of cytokine, 2ndary lymphoid organs, high proliferative potential

CD16 bright: makes lots of perforin and granzyme- cytotoxic, circulate in peripheral blood, low proliferative potential

Question 17

• Why are NK cells considered part of innate system if they can recognize antibodies and MHC?

Answer 17

Receptor type is different

Ligand is different: they don’t recognize the peptide as much but just the Class I MHC, MICA/B which are signals of distress

If there’s no MHC I, the NK kills the cell immediately; whereas cytoxic T cell does not recognize

If there is MHC I, NK inhibits its signal whereas TCR looks more closely

Question 18

What are NK inhibitory receptors v. activating receptors

Answer 18

Inhibitory receptors: recognize MHC I, signal via ITIMs (immunotyrosine activating motifs), recruit phosphatases to prevent cytotoxic response, required for NK cell licencing

Activating receptors: recognize virus/stress assoicated proteins, siganl via ITAMs, use several signaling adaptors

Note that most NK receptors are also on T cells, which is why it’s kind of an artificial distinction to say adaptive v. innate

Balance of engagement with these receptors determines NK decision to activate killing

Question 19

• How do NK cells relate to HIV infection?

Answer 19

NK cells can lyse HIV-infected target cells either directly or by ADCC (antibody dependent cellular cytotoxicity)

HIV has been able to downregulate MHC genes to evade immune control

They have also learned how to become resistant to NK cell cytotoxicity because they jump on CCR5

Question 20

• How do NK cells recognize and kill tumors?

Answer 20

3 pathways:

Granule exocytosis pathway

Death receptor pathway

IFN-gamma, nitric oxide

Question 21

How do uterine NK cells allow the placenta to develop during pregnancy?

Answer 21

During pregnancy, maternal & paternal antigens are expressed in the embryo and placenta

At implantation site, uterine NK cells are predominant leukocyte population

Features of uNK cells: CD56 bright, low cytotoxicity, no CD16, but do secrete lots of cytokines and angiogenic factors

maternal NK cells interact with trophoblast for physiologic placental development