11. differentiation/function CD8+ cells Flashcards
What marker will differentiate T cells from other cell types?
CD3
Which marker will be on and mark a helper T cell?
CD3 and CD4 with MHC II class restiction 66% of cells
Which marker will be on and mark cytotoxic T cell?
CD3, CD8, with MHC I class restiction. 33% of cells
Walk through the process of cytotoxic CD8+ T cell activation.
- DC present peptide antigen to naive T cells in LN
- CD8+ proliferate/differentiate into CTL and memory T cells
- CTL enter circulation and travels to the site of Ag infection
- CTL recognize the Ag at the site, directly kill the target cells
What is required for CTLs to be activated?
- signal 1, from Ag recognition
- Signal 2, from B7-1,-2 costimulator
- Signal 3, comes from cytokines
What will an active CTL secrete?
- granules of perforin and granzymes
2. IFN-gamma, IL-2, -15, -21
What is an important transcription factor that is required during CTL differentiation?
T-bet
What happens if a CTL undergoes differentiation in the absence of T-bet transcription factor?
- the perforins and granzymes and IFN-gamma would not be produced
What is cross-presentation?
- the presentation of an exogenous Ag that is able to be presented to an MHC I class restriction molecule
When would cross-presentation be most beneficial during an immune response?
- latent infection periods
2. infections that impair the function of DC
How does cross-presentation occur?
- Ag moved from the endosome into the cytosol in the APC
- Ag is processed by proteasomes into peptide fragments
- peptide fragments are packed back into endosomes and migrate to different areas
- allows peptide fragment presentation to MHC I class molecules
What role can CD4+ cells have with activation of CD8+ cells?
- help form CD8+ memory cells
- Produce cytokines for CTL differentiation (signal 3)
- Enhance the CD4+ ability to stimulate CTL differentiation
What is APC licensing?
- the use of DC to activate CD8+ cells against a variety of pathogens
How does APC licensing occur?
- CD40 and B7 (DC) bind with CD40L and CD28 (T cell)
- increases efficiency of CTL differentiation
- upregulates B7-1,-2 on the APC
When is the most likely case to have a 3rd signal, from cytokines, introduced for cell signaling?
- weak innate immune responses:
- latent (chronic) viral infection
- organ transplant
- tumor growth - enhance the activity of CTL
Which are the most commonly seen cytokines that act as 3rd stimulatory signals in CD8+ T cell activation?
- IL-2
- IL-12
- IL-15
- IL-21
- IFN-1
What are the effects of IL-2?
- T cell growth
2. CD8+ —> memory and CTL
Of the three subunits in the IL-2, which is most highly expressed before and after T cell activation?
- before: beta and gamma
2. after: alpha
IL-2 gamma has similar structure recognition as what other signaling molecules?
- IL-15, -21
What is the function of IL-12?
- stimulate naive T cell–> CTL
- provides survival/developmental for optimal effector function
- prevents CD8+ cells from exhaustion during chronic infection
What is the function of IFN-1?
- assist with naive T cell stimulation to CTL
2. provides survival/developmental support for optimal effector function
What is the function IL-15?
- formed by tissue macrophage and DC
- promotes survival of memory CD8+ T cells
- costimulate production of IFN-gamma
What is function IL-21?
- formed by active CD4+ T cell
2.
What is IL-2?
- 15kDa polypeptide
2. autocrine function that can have paracrine effects on CD8+ cells
What type of receptor is able to recognize IL-2?
type I cytokines
What is IFN-gamma?
- 25kDa homodimer
- released from NK, Th1, CTL cells
- favors development of Th1 cells and IgG
- upregulates Ag presentation, meaning it’s a large anti-viral component
What type of activating effects does IFN-gamma have?
- activates tissue macrophages
- activates MHC I on all cells
- activates MHC II on professional APC
What is IL-12?
- formed by DC or tissue macropahges
- pro-inflammatory cytokine producer (IFN-gamma, TNF-B)
- prevents CD8+ exhaustion
Which compound is highly expressed in hopes of controlling tumor growth?
- IL-12
2. provides much higher tumor control in terms of numbers and function compared to IFN-1 signals
IL-15 from active CD4+ cells are able to perform what functions?
- stimulate memory CD4, CD8, and naive CD8 cells
2. costimulator for IFN-gamma production
What role do CD8+ T cells have in acute infection?
- secretion of TNF-B, IFN-gamma, perforins, granzymes
2. undergo clonal expansion/differentiation into CTL
What is exhaustion?
- the diminishing effect of CD8+ T cells that occurs in a chronic infection process.
What leads to exhaustion? How do the CD8+ T cells begin to diminish when Ag are still present?
- downregulation of IFN-gamma
- upregulation of PD-1 receptor
- marks for programmed cell death.
What is the theory of HIV chronicity?
- CD8+ T cells experience exhaustion and have upregulation of PD-1 receptor.
- common in Hep C as well.
What are the types of CTL mediated cytotoxicity?
- Fas-FasL mediated
2. Granzyme/perforin mediated
What occurs in granzyme/perforin mediated cytotoxicity?
- Ca, granzyme, perforins are released from a granules
- attack the target cells
- Granzyme B activates caspase-3
- caspase-3 causes DNA degradation
How do CTL only attack the target cell and not affect other surrounding cells?
- the binding creates an immunological synapse where components are secreted and maintained in that synapse to prevent accidental signaling to wrong cells
How does Fas-FasL mediated cytotoxicity work?
- Fas and FasL binding activates signaling cascade
- ultimately caspase-3 is activated
caspase-3 then degrades DNA
Both Fas-FasL and granzyme/perforin mediated cytotoxicity activate caspase-3. What are the signals that will lead to DNA Degradation?
- caspase-3 binds and cleaves ICAD from the ICAD-CAD complex
- ICAD is degraded
- CAD moves into the nucleus to degrade DNA
What is T cell functional polarization?
- ability to take on specific tasks to promote adaptive immune response.
- - effector or regulatory functions depending on response
IL-2R shares common receptor components with which other cytokines?
IL-4, -7, -9, -15, -21
