Differentiation and Functions of CD8 T Cells

Question 1

Which cell type make up 70% of all lymphocytes in the blood?

Answer 1

T cells

Question 2

Which cell type make up 30% of all lymphocytes in the blood?

Answer 2

B cells

Question 3

What is signal 1 in the activation of naive CD8 cells?

Answer 3

Ags

Question 4

What is signal 2 in the activation of naive CD8 cells?

Answer 4

CD28-CD80 costimulation

Question 5

Activated CTLs contain numerous granules called lysosomes. What do lysosomes contain?

Answer 5

> perforin
granzymes

used to kill other cells

Question 6

What do activated CTLs secrete?

Answer 6

Cytokines, mostly IFN-gamma, that potently activate macrophages.

Question 7

What transcriptional factor does CTL differentiation involve?

Answer 7

T-bet

similar to activation of Th1 cells

Question 8

What does the transcriptional factor, T-bet, regulate?

Answer 8

Transcription of genes encoding:
> perforin
> granzymes
> IFN-gamma

Question 9

What is the “magic of cross-presentation”?

Answer 9

Extracellular Ags are processed and presented within class II MHC (classical), but they are also presented in association with class I MHC.

Question 10

Extracellular Ags are processed and presented within class II MHC (classical), but they are also presented in association with class I MHC. HOW??

Answer 10

Ag CROSS-PRESENTATION -> some viral Ags are released from phagosome in cytoplasm of DC and then presented within class I MHC.

The same cross-presenting APC also display microbial peptides within class II MHC for CD4+ helper T cells.

Question 11

Are CD4 helper T cells more important for generation of CD8 memory T cells or the differentiation of naive CD8 T cells into effector CTLs?

Answer 11

More important for the generation of CD8 memory T cells.

Question 12

When does licensing of the APC occur?

Answer 12

When the CD4 T cell recognizes Ag presented by an MHC class II APC and delivers activating signals through CD80/CD86 and CD40.

Question 13

What happens when the CD4 T cell recognizes Ag presented by an MHC class II APC and delivers activating signals through CD80/CD86 and CD40?

Answer 13

LICENSING of the APC

Question 14

Which activated cell type expresses CD40L?

Answer 14

Activated CD4 Th cells express CD40L.

Question 15

What does the interaction of CD40-CD40L upregulate the expression of?

Answer 15

Expression of CD80/CD86 on professional APCs which makes them more efficient at stimulating the differentiation of CD8 T cells.

Question 16

What does the expression of CD80/CD86 on professional APCs make them more efficient at?

Answer 16

More efficient at stimulating the differentiation of CD8 T cells.

Question 17

Does the mechanisms of APC licensing require that CD4 and CD8 T cells be in contact with the APC at the same time?

Answer 17

No - it does not require that CD4 and CD8 T cells be in contact with APC at the same time.

Question 18

What is signal 3 to enhance activation of CTLs?

Answer 18

CD4 helper T cells provide signal 3 in form of cytokines which enhance activation of CTLs.

Question 19

True of False:

CD4 helper T cells are required for CD8 T cell responses when relatively weak innate immune reactions are evoked by latent viral infections, organ transplants, and tumors.

Answer 19

True

Question 20

What is the role of IL-2 in CTL activation?

Answer 20

promotes PROLIFERATION and DIFFERENTIATION of CD8 T cells into CTLs and MEMORY CELLS.

CD8 T cells may express high levels of the alpha subunit of IL-2R after activation. Shares a common receptor component (the gamma chain) with IL-15 and IL-21.

Question 21

What is the role of IL-12 and type I IFNs in CTL activation?

Answer 21

stimulate the DIFFERENTIATION of naive CD8 T cells into effector CTLs.

Haive CD8 T cells proliferate in response to TCR and CD28 signals, but require IL-12 or type I IFN for SURVIVAL and DEVELOPMENT of optimal effector functions.

Question 22

What is the role of IL-15 in CTL activation?

Answer 22

Produced by DCs and tissue macrophages.
Important for the SURVIVAL OF MEMORY CD8 T CELLS.

mice lacking IL-15 show a significant loss of memory CD8 T cells.

Question 23

What is the role of IL-21 in CTL activation?

Answer 23

produced by activated CD4 T cells play a role in the induction of CD8 T cell memory and the prevention of CD8 T cell exhaustion.

Question 24

What is a major feature of IL-2 in how it operates?

Answer 24

autocrine loop

Question 25

What other cytokines does IL-2 share a common receptor component (the gamma-chain)?

Answer 25

IL 4, 7, 9, 15, and 21

Question 26

True of False: | Local release of IL-2 can lead to activation of nearby CD8 T cells in a paracrine fashion.

Answer 26

True

Question 27

Is CD4 T cell-derived IFN-gamma a homodimer?

Answer 27

Yes

Question 28

What cell types release IFN-gamma?

Answer 28

- Th1 cells - CTLs - activated NK cells

Question 29

What is IFN-gamma a potent activator of?

Answer 29

Potent activator of macrophages inducing an increase in metabolic, phagocytic, and killing activity.

Question 30

What does IFN-gamma have the ability to do?

Answer 30

Increase class I MHC molecule expression on a range of cell types and induce expression of class II MHC molecules on professional APCs. **This may be an important component of antiviral protection, since it up-regulates Ag presentation of viral targets by infected cells.**

Question 31

What does IFN-gamma favor the development of?

Answer 31

Th1 cells and B cell differentiation biasing the production of immunoglobulin in favor of IgG and away from IgE.

Question 32

What cell types produce IL-12?

Answer 32

DCs and macrophages

Question 33

What does IL-12 do?

Answer 33

Profound effect of inducing naive CD4 T cells to differentiate into Th1 effector cells.

Question 34

The balance between which cytokines determines whether cells become Th1 or Th2?

Answer 34

IL-12 and IL-4

Question 35

What does IL-12 promote the production of?

Answer 35

IFN-gamma and TNF-beta by CD4+ and CD8+ T cells.

Question 36

Does IL-12 assist in the prevention of CD8 T cell exhaustion?

Answer 36

Yes

Question 37

Does IL-12 activate NK cells?

Answer 37

Yes

Question 38

Which cells produce the primary soruce of IL-15?

Answer 38

Activated tissue macrophages and mature DCs.

Question 39

What other cytokine does IL-15 share a similar biologic properties with?

Answer 39

IL-2 - have shared receptor signaling components.

Question 40

What does IL-15 simulate the proliferation of?

Answer 40

Memory CD4+ and CD8+ and naive CD8+ T cells.

Question 41

Can IL-15 costimulate innate immune IFN-gamma production?

Answer 41

Yes

Question 42

In vitro, what type of T helper cell does exogenous IL-15 favor?

Answer 42

Th1 T-cell

Question 43

Once a CTL is activated by presentation of a viral Ag via a DC, what does the CTL secrete?

Answer 43

- TNF-beta - IFN-gamma - cytotoxic perforn and granzymes

Question 44

After viral clearance, what happens to CD8+ T cells?

Answer 44

Undergo an extensive contraction phase, mediated by apoptosis.

Question 45

What do exhausted CD8+ T cells show?

Answer 45

Reduced production of IFN-gamma and increased expression of PD-1 inhibitory receptor.

Question 46

What do inhibitory signals from PD-1 block the activation of?

Answer 46

CTLs **PD-1 mediated T cell exhaustion may contribute to the chronicity of HIV and hepatitis C virus**

Question 47

True or False: Anti-PD-1 Abs are effective in the immuno-therapy of tumors.

Answer 47

True

Question 48

True or False: CTLs are injured during the killing of target cells.

Answer 48

False - CTLs are not injured during the killing of targets.

Question 49

What are the two major mechanisms of killing by CTLs?

Answer 49

> Fas-FasL-Mediated Apoptosis > Granzyme-Mediated Apoptosis

Question 50

Threre are granzymes A, B, and C, which are serine proteases. Which is the only one shown to be required for CTL cytotoxicity in vivo?

Answer 50

Granzyme B

Question 51

What complement protein is perforin homologous to?

Answer 51

C9 complement protein.

Question 52

What is the function of the sulfated proteoglycan serglycin that is also contained in granules released by CTLs?

Answer 52

Assembles a complex containing granzymes and perforin.

Question 53

By what mechanism does perforin and granzymes enter the target cell to kill it?

Answer 53

Perforin insertion into the target cell membrane elicits a membrane repair process in the target cell that lead to internalization of both the perforin and granzymes in to endosomes. When in the target cell, GRANZYME B activates caspase-3 that triggers apoptosis.

Question 54

Draw out the Fas-FasL -Mediated Apoptosis mechanism.

Answer 54

Keep working hard!!

Question 55

What is the mechanism of CD8+ CTLs in host defense against intracellular bacteria?

Answer 55

> CD8 T cells cooperate with CD4 T cells and in defense against intracellular microbes. > Intracellular bacteria such as L. monocytogenes are phagocytized by macrophages and may survive in phagosomes and escape in the cytoplasm. > CD4 T cells respond to class II MHC-associated peptide Ag derived from the intravesicular bacteria nad produce IFN-gamma and IL-2. > CD8 T cells respond to class I-associated peptides derived from cytosolic Ags and kill the infected cells.