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Chapter 14b


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principal rles of cell-mediated immunity:
1. cells with intracellular pathogens
2. cells with altered genes (tumor)
What cell types are involved in cell-mediated effector responses?
specific cells -> Thelper, Tcytotocic

nonspecific -> NK cells, macrophages, neutrophils, and eosinophils.
How is an effector response activated in general?
By activation of EFFECTOR cells - these have different activation requirements than naive.
How is activation of naive cells different from that of effector cells?
Naieve have low levels of CAMs, require co-stim B7-CD28 signal 2, and traffic in HEV.

Effector cells already have high CAM levels, don't require co-stim signal, and traffic in 3iary lymphoid tissues and inflammatory sites.
3 steps in activation of p-CTLs:
1. Binding TcR with Ag presented on MHC1. Causes IL-2receptor expression, and secretion of some IL-2 itself.

2. Co-stimulatory signal
3. Il-2 binding Il-2R induces differentiation and proliferation.
How do Th1 cells aid in the effector response?
Ag presentation stimulates IL-2 secretion. Il-2 binds receptor and self-stimulates.

Il-2R binding causes prolif/differ, produces IL-2 to help CTL activation.

Thelpers give Cytokines to Stim. CTLs
what is the purpose of activating CTLs?
To make them produce GRANULES which contain the ingredients for killing target cells
How does Th1 and CTL activation stop?
When Antigen presentation declines, secretion of Il-2 cytokines stops, and activation stops.
Do Thelper cells really help naieve or memory CTLS?
Naive. Because naive need extra Il-2 to activate them, but memory produce enough IL-2 to activate themselves.

Th cytokines also stimulate B7 expression, for the co-stimulatory signal necessary for NAIVE activation.
What is necessary for activation of naive Tcells, but not memory
Co-stimulatory signal
Thelper cells which secrete IL-2 and upregulate B7 on APC
What is LFA?
a cell adhesion molecule on Tcell surfaces. vital for binding of memory Tcell to target.
what change occurs in LFA-1 when antigen is presented to effector CTLs?
During initial hugging of target, CTL scans surface to make sure Ag is correct. If so,

LFA-1 affinity increases and binds tightly to ICAMs on target.
What two membrane-associated molecules are vital for CTL-cytotoxicity to even start?
ICAMs on target
LFA-1 on CTL

If antigen is correct, LFA-1 affinity increases, ICAMS bind tightly.
4 steps in CTL-cytotoxic death
1. Conjugate formation (scan surface, LFA-1 affinity increase, bind ICAMs)
2. CTL cytoplasmic rearrangement (easy access of granules for target)
3. CTL granule exocytosis (into space between cells, perforin makes holes to let granzymes into target)
4. Dissociation (CTL goes to kill something else, while target undergoes Apoptosis).
2 pathways that result in target cell APOPTOSIS
1. Fas
2. Perforin/granzyme.
How does fas induce apoptosis?
CTLs have Fas-ligand. when it binds Target cells, it activates procaspase-8
How does granzyme/perforin activate apoptosis?
perforin gets granzyme where it needs to be.

granzyme activates procaspase-8
Purpose of NK cells:
first-line defense against VIRUS infected cells
Why are NK cells firstline innate Viral defense?
Constitutive levels of granules.
produce antiviral cytokines
Why are NK cells extremely important?
-Allow neutralization of virus while a specific Tcell response is being generated.

EARLY response
How are NK cells stimulated to produce antiviral cytokines?
Virus-infected cells secrete IFN-a and IFN-B, and these stimulate NK activity.
when is the NK response seen? why?
When is the CTL response seen?
(in a timecourse of viral infection)
First seen: IFNa/b from day 0-4

2nd seen: NK cell response day 0-6
NK wave closely follows cytokine from infected cell

3rd seen: Specific CTL response day 6-10
What are IFNa/b?
Antiviral cytokines secreted by virus-infected cells.

stimulate NK activity
can one survive viral infection if they lack adaptive immunity?
YES; NK cells can neutralize the infected cells, but the patient will be susceptible to infection
How do NK cells kill?
Same mechanism as CTLs -> perforin/granzyme.
NK cells are INNATE; how do they know who to kill? (how do they recognize target cells)
1. Depend on Ab to direct them to target cells (ADCC)

2. Opposing-signal model
Principal of opposing-signal model:
1. NK cells have ligand for activation receptor.
2. Target cells have activation receptor
Healthy cells have MHC1 which sends inhibitory signal, over-rides Activ. sig

Sick cells have less MHC1, so only the activation signal gets sent; activates KILLING (via Fas or Granzyme)
What types of cells mediate ADCC?
How does ADCC work?
Cytotoxic cells (NK, neutro, eosino..) have Fc receptors for Antibodies.

Target cells have Ab bound to their surface antigens.

FcR bind Ab Fc region, release lytic enzymes and harm to target cell.

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