Cell Mediated Cytotoxicity Flashcards
Humoral immunity
mediated by antibody and is responsible for protecting the extra-cellular environment from pathogens and toxins
Cell mediated immunity
recognizes pathogen-infected cells or cells that have undergone genetics alterations (tumor cells) and kills them
essential defense against intracellular pathogens, including viruses, some bacteria and some parasites.
Mediators of cell-mediated immunity
Antigen non-specific effector cells: Natural killer (NK) cells Macrophages Neutrophils Eosinophils
Antigen specific effector cells:
CD8+ T cells (cytotoxic T cells, CTLs, Tc cells)
CD4+ T cells (helper T cells, Th cells)
CTL-P activated by
licensed APC
APCs can be licensed by
Th1 or Th17 CD4+ cells (via CD40/CD40L) as well as by engagement of PAMPs with TLRs
Requirement for CD4+ T cell help for license APC? Generate CD8+ memory?
No for license APC
Yes for generate memory
Activation to effector CD8+ cell
Antigen-specific signal, transmitted by the TCR upon recognition of the proper peptide: MHC Class I complex presented by a licensed APC.
Co-stimulatory signal is transmitted by CD28:CD80/CD86 interaction between the CTL-P cell and the licensed APC.
IL-2 secreted by a Th1 or Th17 CD4+ T cell or the CTL itself results in the proliferation and differentiation of the antigen-activated CTL-P cell to a fully active CTL.
Naive CTL-P
Does not express IL-2 or the high affinity IL-2R (CD25) until after activation (no proliferation).
Expresses high levels of L-selectin and CCR7 (homing and retention in the lymph node).
Expresses low levels of CD44 and LFA-1.
No cytotoxic activity
Effector CTL
Expresses high affinity IL-2R (CD25) and synthesizes IL-2.
Expresses low levels of L-selectin and CCR7.
Expresses high levels of CD44 and LFA-1 (homing and retention at sites of inflammation)
Exhibits cytotoxicity (starts to produce perforin and granzyme).
Memory CTL Cells
cells may not require Th1 CD4+ T cell help to reactivate.
Requires only low levels of IL-2 (can be produced by activated CTLs) for memory CTLs to become mature effector CTLs
CCR7 and L-selectin
homing and retention in the lymph node
CD44 and LFA-1
homing and retention at sites of inflammation
CTL binding of the target cell
TCR-CD3 complex of CTL recognizes MHC/peptide
LFA-1 on CTL binds ICAMS
Antigen activation: LFA-1 –> high affinity then back to low affinity in 10 minutes
CTL killing mechanisms
Perforin granzyme secretions
Fas ligand
TNFa production and secretion
Perforin and granzyme
Perforin molecules form a pore on target cell membranes.
Granzyme molecules activate apoptosis by cleavage of caspases.
Fas ligand protein
Membrane-bound FasL binds to Fas on the membrane of the target cells and initiates killing
Activates apoptosis by cleavage of caspases
Caspase cascade
Get 8, 2, 1 cleaved - all go to 3, 6, 7
8 also goes to Bid –> tBid at mitochondria –> cytochrome C –> caspase 9 –> 3,6,7
3, 6, 7 at high levels trigger apoptosis
NK cells play major roles in killing
virus-infected cells, intracellular pathogen-infected cells and tumor cells
Some NK cells can produce
IFN-gamma
IFN-γ tilts the immune response toward Th1 cells by inhibiting Th2 cells and inducing IL-12 production by macrophages and dendritic cells.
IFN-γ can activate macrophages (M1 – angry) and NK cells.
NK cell activity is stimulated by
IFN-α, IFN-β, IFN-γ, TNF-α, and IL-15, IL-12
TYPE 1 INTERFERONS AND IL-12
timing of NK cells
early - make IFNa and IFNb –> NK cells
before CTLs
Nk cells express
CD16 (FcγRIIIA) and NKRs.
NK cells do/do not undergo receptor gene rearrangement
DO NOT (no TCR or CD3)
NK kill is/is not MHC restricted
IS NOT (no CD4 or CD8)
