Flashcards in Cell Mediated Cytotoxicity Deck (26)
Cells that are CD25+. . .
. . .have high affinity IL-2 receptors!!
T cell giving instructions back to the APC
Where does IL-2 bind?
What activates CTLs?
What sequence signals are required for the activation of CTL effector cells?
1. Antigen-specific signal, transmitted by the TCR upon recognition of the proper peptide/MHC Class I complex presented by a licensed APC
2. Co-stimulatory signal is transmitted by CD28/CD80/86 interaction between the CTL-P cell and licensed APC
3. IL-2 secreted by Th1 or Th17 CD4+ cell or the CTL itself result in the proliferation and differentiation of the antigen-activated CTL-P cell to fully active CTL.
What effector molecules are produced by effector CTLs?
-High affinity IL-2R (CD25) and synthesizes IL-2
-Low levels of L-selectin and CCR7 (so they can escape lymph node - opposite naive CTL-P)
-High levels of CD44 and LFA-1 (homing and retention to sites of inflammation)
-Exhibits cytotoxicity (starts to produce perforin and granzyme)
What is NK cells major role?
Killing virus-infected cells, intracellular pathogen-infected cells and tumor cells
What stimulates NK cell activity?
IFN-alpha (Type I interferon), IFN-beta (Type II interferon), IFN-gamma, TNF-alpha, IL-15
-NK cells are recruited within 3 days of viral infection, before CTLs
What two things do NK cells do?
-Recognize lack of self
-Recognize self + foreign antigen
What do NK cell release/produce?
-It tilts the immune response toward Th1 cells by inhibiting Th2 cells and inducing IL-12 production by macrophages and dendritic cells
-IFN-gamma can activate macrophages (M1 - angry) and NK cells
What are NK cells like in the bloodstream?
-Make up 5-10% of circulating lymphocytes
-90% of blood NK cells are CD56low --> most effective killers of target cells (10% CD56high - no granules - release cytokines like IFN-gamma)
What cell surface proteins of CD4+ T cells and APCs are important in the process of "licensing" the APC for cross-presentation of antigen?
TCR on Th1 or Th17 binds to MHC Class II on APC.
CD40 on APC binds CD40L on Th1 or Th17. This interaction gives the APC instructions about what cytokines it can release.
What happens in Licensing APCs?
-Licensing APCs requires interaction with CD4+ Th1 or Th17 or direct interaction with a pathogen - TLR molecule
-Presentation of antigen to the CTL-P through MHC Class I can only take place after the APC has "found" a pathogen or has been "told" that is has found a pathogen. This acts as a control to prevent self-recognitation by CTLs.
-Infection of a dendritic cell by a virus can also assist in the presentation of antigen associated with MHC Class I molecules.
How do CD8+ T cells bind target cells?
-TCR-CD3 complex on CTL recognizes the peptide/MHC Class I complex on the target cell
-LFA-1 on the CTL binds to ICAMs on the target cell
-Antigen activation converts the LFA-1 from a low affinity state to a high affinity state for better binding
-After about 5 to 10 minutes, LFA-1 returns to a low-affinity state, resulting in the dissociation of the CTL from the target cell.
What are the mechanisms by which CTLs kill?
1. Perforin & granzyme secretions:
--Perforin molecules form a pore on target cell membranes
--Granzyme molecules activate apoptosis by cleavage of caspases (granzymes flow through perforin pore)
2. Fas ligand protein on the cell membrane surface:
--Membrane-bound FasL binds to Fas on the membrane of the target cells and initiates killing
--Activates apoptosis by cleavage of caspases
3. CTLs can also kill by TNF production and secretion
What are the two pathways to activate apoptosis?
1. FasL binds Fas and activates Caspase-8 (through FADD and procaspase-8) --> Bid gets stimulated which causes mitochondria to release cytochrome C which binds to Apaf-1 and caspase-9 --> This complex activates Caspase-3 which then activates apoptotic effectors --> Caspase-8 also directly activates caspase-3
2. Granzyme gets into the cell and activates Bid and produces procaspase-3 (inactive) --> same progression as FasL
What cell surface proteins do NK cells express?
CD16 (FcgammaRIIIA) and NKRs
Do NK cells need to be educated in the thymus?
Do NK cells undergo rearrangement of receptor genes?
NO - they don't make TCR or CD3
Do NK cells have memory?
They may have. . .?
Like CD8+ T cells, is NK killing MHC restricted?
NO - no CD4 or CD8 corrector binding requirement
How is NK cell killing similar to CTL killing?
1. FasL expressed not the surface can kill cells expressing Fas
2. Perforin and granzyme released from granules
3. TNF expressed on the surface and secreted
What is the process of NK cell recognition of cell targeted for killing?
-NK cells kill cells that mask the presence of foreign antigen on MHC Class I.
-If cell's ligand binds the NK cells activating receptor and there is no 'negative signal from MHC Class I (no MHC Class I present!) binding to Ker ligand, then the NK cell will kill!
-If the NK cell binds Class I MHC to its inhibitory receptor/Ker ligand and binds the cells ligand to the NK cell's activating receptor, it will not kill.
What effector cells are associated with ADCC (antibody-dependent cell mediated cytotoxicity)?
How does ADCC happen?
1. Effector cells bind antigen via the antibody, through the Fc receptor.
2. Killing is mediated by cytolytic enzyme release by macrophages, neutrophils, and eosinophils.
3. TNF release by NK cells, monocytes and macrophages.
4. Perforin release by NK cells and eosinophils.
5. Granzyme release by NK cells.