Flashcards in Lecture 23 - Cell-mediated Effector Function Deck (57):
In general, what is required for pathogen clearance?
An adaptive immune response
(Ab and CTLs)
What are the two arms of the adaptive immune system?
Describe the features of each
• B cell mediated
• Extracellular pathogens
• T cell mediated
• Intracellular pathogens
What are the two subsets of conventional T cells?
2. "Helper" T cells
What are the principle effector mechanisms of activated T cells?
2. Membrane associated effector molecules
3. Soluble cytokines
What are the categories of effects of cytokines?
• Cell-cell contact
• Membrane cytokines
• Chemotactic effects
Compare T-cell effector functions for the following:
• Intracellular pathogens in cytosol
• Intracellular pathogens in phagocytic compartments
• Small extracellular pathogens
• Large extracellular pathogens
Intracellular pathogens in cytosol:
• CD8+ T cell mediated killing
Intracellular pathogens in phagocytic compartments:
• Th1 mediated IFN-γ responses
Small extracellular pathogens:
• Th17 mediated neutrophilic responses
Large extracellular pathogens:
• Th2 mediated IL-5 and IgE responses
What are IFN-γ responses good for?
Intracellular pathogens in phagocytic compartments
By triggering respiratory burst in macrophages
What response is best for small extracellular pathogens?
Th17 mediated neutrophilic responses
What response is best for large extracellular pathogens?
Th2 mediated IL-5 and IgE responses
Which response is best for intracellular pathogens?
• CTL killing
In phagocytic compartments:
How do T cells get into the tissue?
Why would they need to do this?
After activation in the secondary lymphoid organs, they need to recirculate to the infected tissue to perform their effector function
• Release of cytokines from infected tissue
• Expression of adhesion molecules on the T cells and endothelial cells
→ Rolling: selectins
→ Activation: chemokines
→ Adhesion: integrins
→ Diapedesis: chemokines
• Draining of T cells into efferent lymphatics → blood → tissue
Describe the molecule interaction during T cell rolling in migration to the skin
On vascular endothelium:
Describe the molecule interactions in the 'activation' step of T cell migration to the skin
Describe the molecule interactions in the 'Adhesion' step of T cell migration to the skin
What brings about the expression of selectins and integrins on endothelium?
Produced by innate cells in the infected tissue
Describe the molecule interactions in the 'Rolling' step of T cell migration to the gut
• α4β7 integrin
Describe the molecule interactions in the 'Activation' step of T cell migration to the gut
Chemokine release by enterocytes:
Describe the molecule interactions in the 'Adhesion' step of T cell migration to the gut
T cells: α4β7 integrin
Which chemokine is involved with T cell homing to the gut?
What is the receptor for this?
What is the effect of the 'activation' step in T cell homing?
Conformational change in integrins → Adhesion
Describe tissue specific migration to the skin
1. Vit D metabolites in skin
2. DC experiences these metabolites and changes phenotype
3. Travels to regional lymph node
4. Skin imprinted DC interacts with naïve T cell and induces CCR10, CCR4, P- and E-selectin ligand (i.e. CD43 and PSGL) expression on the T cells
4. T cells home to skin
Describe 'imprinting' and T cell homing to the gut
1. Dietary vitamin A present in interstitial tissue in gut
2. DC experience these metabolites and changes phenotype
3. DC draining to LN
4. 'Gut' imprinted DC interacts with naïve T cell and induces CCR9 and α4β7 expression
5. T cells home to gut tissue
Compare lymphocyte infiltrate in the dermis of infected and non-infected mice
• Low overall levels
• No CTLs
• A few helper T cells
• High levels of T cell infiltrate
What are Th1 good for?
Intracellular pathogen responses through production of IFN-γ
Which cytokines lead to differentiation into Th1?
(released from DC)
What is the effector function of IFN-γ?
1. Macrophage activation
→ increased antigen presentation → increased CTL activation
2. Killing of intracellular pathogens
Through respiratory burst
3. Expression of inflammatory mediators by infected cell
→ recruitment of T cells to site of infection
What are Th2 good for?
How are Th2 induced?
IL-4 released from Mast cells, Eosinophils (?)
Which cytokines do Th2 produce?
Describe the effector function of Th1
1. Macrophage activation
3. Proliferation of T cells
4. Differentiation of other cell types in BM
5. Endothelial activation
• Lymphotoxin (LT)
6. Chemotactic events
(recruitment of more inflammatory cells)
Describe the effector function of Th2
1. B cell IgE production
2. Mast cell degranulation
• Through IgE production
3. Barriers: mucous production in GIT and peristalsis
4. Eosinophil activation
5. Alternative macrophage activation
→ enhanced fibrosis / tissue repair
Which cytokines stimulate the differentiation into Th17?
IL-6 & TGF-β
Which transcription factors are important for Th17?
Which cytokines do Th17 produce?
What are the effector functions of Th17?
1. Neutrophilic responses
2. Increased barrier function
Outline the effector function mechanism of CTLs
1. Non-specific adhesion
• Integrins etc
• Does not activate the T cell
2. Specific recognition
• MHC I/peptide complex - TCR
(peptide antigen from e.g. virus)
• Brings about activation of the T cell
3. Activation of T cell
• Cytoskeletal changes in the T cell
• Golgi apparatus polarised towards infected cell
3. Granule release
• Via exocytosis
• Release only towards infected cell
4. Target cell death
What are the cytotoxic substances released by CTLs?
What is the role of each?
• Form pores in membranes
• Aids delivery of other cytotoxic mediators (granzymes)
• Induces apoptosis through activation of pro-caspase 3 and BID
Both these need to be present for killing to occur
To a lesser degree:
• Antimicrobial found only in humans
• The scaffold for perforin and granzyme
What is the structure of the complex released by CTLs?
• Forms a complex with perforin and granzymes
• Complex then released towards virally infected cell
What is the function of granulysin?
• Only in humans
• Induces apoptosis
• Also has antimicrobial actions
Describe the mechanism of action of granzymes
• Interacts with Bax and Bak
→ Pore formation in mitochondria
→ Loss of cytochrome c into cytosol
2. Pro-caspase 3
• Activated pro-caspase 3 activates DNAases
• Fragmentation DNA in the cell
Outcome: Target cell killed
Where are Bax and Bak located?
On the outer membrane of mitochondria
What are the features of the cell death induced by CTLs?
• No adjacent inflammation
• No release of pathogens
Describe the Fas-FasL pathway
• Alternative mechanism of T cell killing
• Carried out by Th cells
• Effector T cell expresses Fas L
• Target cell expresses Fas
1. Interaction of the ligands
2. Intracellular Death domains on Fas come together
3. Recruitment of FADD
4. Activation of caspase 8 by FADD
What is the role of the death domain?
Intracellular part of the Fas receptor
1. Recruits caspase 8 when Fas is ligated
2. Auto-activation of caspase 8
3. Cell death through apoptosis
What is happening in Autoimmune lymphoproliferative disease?
• Mutation in Fas-FasL pathways
• Dysfunctional apoptosis of lymphocytes
• Enlarged LN, full of T cells that were not removed at the end of an immune response
What is the first interaction between virally infected cells and CTLs?
Which Th subsets are important for barrier protection?
Describe, in general, effector T cell homing to specific tissues
Specific compound in the tissue drained by certain LNs
These compounds activate the lymphocytes in these LNs, and induce them to home back to these tissues
Which component of CTL granules is only found in humans?
Which Th subsets activate macrophages?
Th1: M1 inflammatory macrophages
Th2: M2 fibrotic macrophages
When is Fas killing usually employed?
Apoptosis of effector T cells after the pathogen has been cleared
Describe T cell help for macrophages
1. Infected macrophage is expressing bacterial peptide in the context of MHC class II
2. Th1 recognises the MHC II:peptide complex with its TCR
3. Th1 releases IFN-γ onto macrophage which expresses the receptor
4. CD40L on Th1 ligates CD40 on macrophage
5. Macrophage is stimulated to undergo respiratory burst, and is better able to kill the pathogen in its endocytic compartments
After activation in LNs, which molecules do T cells up-regulate, and which do they down-regulate?
• CCR4/10 (skin)
• CCR9 (gut)
• α4β7 integrin (gut)
• CD43 (skin)
• LFA-1, VLA-1 (skin)
What are CD62P and CD63E?
P- and E-selectin
Expressed on vascular endothelium in skin when infected
Recruitment of skin-tropic activated T cells (expressing PSGL1 and CD43 )
What is the ligand for CD62E?
What is the ligand for CD62P?