Differentiation and Functions of CD8 T Cells Flashcards
Which cell type make up 70% of all lymphocytes in the blood?
T cells
Which cell type make up 30% of all lymphocytes in the blood?
B cells
What is signal 1 in the activation of naive CD8 cells?
Ags
What is signal 2 in the activation of naive CD8 cells?
CD28-CD80 costimulation
Activated CTLs contain numerous granules called lysosomes. What do lysosomes contain?
> perforin
granzymes
used to kill other cells
What do activated CTLs secrete?
Cytokines, mostly IFN-gamma, that potently activate macrophages.
What transcriptional factor does CTL differentiation involve?
T-bet
similar to activation of Th1 cells
What does the transcriptional factor, T-bet, regulate?
Transcription of genes encoding:
> perforin
> granzymes
> IFN-gamma
What is the “magic of cross-presentation”?
Extracellular Ags are processed and presented within class II MHC (classical), but they are also presented in association with class I MHC.
Extracellular Ags are processed and presented within class II MHC (classical), but they are also presented in association with class I MHC. HOW??
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.
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?
More important for the generation of CD8 memory T cells.
When does licensing of the APC occur?
When the CD4 T cell recognizes Ag presented by an MHC class II APC and delivers activating signals through CD80/CD86 and CD40.
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?
LICENSING of the APC
Which activated cell type expresses CD40L?
Activated CD4 Th cells express CD40L.
What does the interaction of CD40-CD40L upregulate the expression of?
Expression of CD80/CD86 on professional APCs which makes them more efficient at stimulating the differentiation of CD8 T cells.
What does the expression of CD80/CD86 on professional APCs make them more efficient at?
More efficient at stimulating the differentiation of CD8 T cells.
Does the mechanisms of APC licensing require that CD4 and CD8 T cells be in contact with the APC at the same time?
No - it does not require that CD4 and CD8 T cells be in contact with APC at the same time.
What is signal 3 to enhance activation of CTLs?
CD4 helper T cells provide signal 3 in form of cytokines which enhance activation of CTLs.
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.
True
What is the role of IL-2 in CTL activation?
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.
What is the role of IL-12 and type I IFNs in CTL activation?
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.
What is the role of IL-15 in CTL activation?
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.
What is the role of IL-21 in CTL activation?
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.
What is a major feature of IL-2 in how it operates?
autocrine loop
What other cytokines does IL-2 share a common receptor component (the gamma-chain)?
IL 4, 7, 9, 15, and 21
True of False:
Local release of IL-2 can lead to activation of nearby CD8 T cells in a paracrine fashion.
True
Is CD4 T cell-derived IFN-gamma a homodimer?
Yes
What cell types release IFN-gamma?
- Th1 cells
- CTLs
- activated NK cells
What is IFN-gamma a potent activator of?
Potent activator of macrophages inducing an increase in metabolic, phagocytic, and killing activity.
What does IFN-gamma have the ability to do?
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.
What does IFN-gamma favor the development of?
Th1 cells and B cell differentiation biasing the production of immunoglobulin in favor of IgG and away from IgE.
What cell types produce IL-12?
DCs and macrophages
What does IL-12 do?
Profound effect of inducing naive CD4 T cells to differentiate into Th1 effector cells.
The balance between which cytokines determines whether cells become Th1 or Th2?
IL-12 and IL-4
What does IL-12 promote the production of?
IFN-gamma and TNF-beta by CD4+ and CD8+ T cells.
Does IL-12 assist in the prevention of CD8 T cell exhaustion?
Yes
Does IL-12 activate NK cells?
Yes
Which cells produce the primary soruce of IL-15?
Activated tissue macrophages and mature DCs.
What other cytokine does IL-15 share a similar biologic properties with?
IL-2 - have shared receptor signaling components.
What does IL-15 simulate the proliferation of?
Memory CD4+ and CD8+ and naive CD8+ T cells.
Can IL-15 costimulate innate immune IFN-gamma production?
Yes
In vitro, what type of T helper cell does exogenous IL-15 favor?
Th1 T-cell
Once a CTL is activated by presentation of a viral Ag via a DC, what does the CTL secrete?
- TNF-beta
- IFN-gamma
- cytotoxic perforn and granzymes
After viral clearance, what happens to CD8+ T cells?
Undergo an extensive contraction phase, mediated by apoptosis.
What do exhausted CD8+ T cells show?
Reduced production of IFN-gamma and increased expression of PD-1 inhibitory receptor.
What do inhibitory signals from PD-1 block the activation of?
CTLs
PD-1 mediated T cell exhaustion may contribute to the chronicity of HIV and hepatitis C virus
True or False:
Anti-PD-1 Abs are effective in the immuno-therapy of tumors.
True
True or False:
CTLs are injured during the killing of target cells.
False - CTLs are not injured during the killing of targets.
What are the two major mechanisms of killing by CTLs?
> Fas-FasL-Mediated Apoptosis
> Granzyme-Mediated Apoptosis
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?
Granzyme B
What complement protein is perforin homologous to?
C9 complement protein.
What is the function of the sulfated proteoglycan serglycin that is also contained in granules released by CTLs?
Assembles a complex containing granzymes and perforin.
By what mechanism does perforin and granzymes enter the target cell to kill it?
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.
Draw out the Fas-FasL -Mediated Apoptosis mechanism.
Keep working hard!!
What is the mechanism of CD8+ CTLs in host defense against intracellular bacteria?
> 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.
