Lecture 23 - Effector Mechanisms in T Cell Responses Flashcards
Primary target of cellular immunity
Intracellular pathogens
Primary target of humoral immunity
Extracellular pathogens
Response to small extracellular pathogens, such as bacteria and fungi
Th17 neutrophilic response
Response to large extracellular parasites, eg: helminth worms
Th2-mediated IL-5 and eosinophil response
Response to cytosolic intracellular pathogens
CD8+
Response to intracellular pathogens in phagocytic compartments
Th1-mediated IFNg responses
What does LFA-1 stand for?
Leukocyte function antigen 1
Which cells express selectins?
Cells to which T cells will adhere
Which cells express E- and P-selectin?
Epithelial cells
Which T cell surface molecule binds to E- and P-selectin?
PSGL-1
Which selectins do epithelial cells express?
P- and E-selectins
Activation signals secreted by epithelial cells
CCL17, CCL27
Epithelial cell adhesion molecules
ICAM-1, VCAM-1
Which cells express ICAM-1 and VCAM-1?
Endothelial cells
What induces epithelial cells to express T cell adhesion molecules?
TNFa, IFNg
What detects CCL17 and CCL27?
CCR4 and CCR10
What binds ICAM-1?
LFA-1
What binds VCAM-1?
VLA-4
Factor expressed by endothelial cells in GALT for T cell rolling
MAdCAM-1 and P-selectin
What expresses MAdCAM-1 and P-selectin?
Endothelial cells in GALT
MAdCAM-1 ligand for rolling
Inactive alpha4 beta7 integrin
T cell activation factor in GALT
CCL25 (produced by enterocytes)
What expresses CCL25?
Enterocytes.
Activates T cells in GALT
Factor expressed by GALT endothelial cells for adhesion
MAdCAM-1
MAdCAM-1 ligand for adhesion
Active alpha4 beta7 integrin
How is tissue-specific information imprinted in organ-dwelling lymph nodes?
A factor from the organ that the lymph node drains biases T cells to express certain chemokine receptors
Example of imprinting of tissue-specific information in an organ-dwelling lymph node
1)
2)
3)
1) In a lymph node that drains the skin, vitamin D metabolites act on dendritic cells and stromal cells
2) DCs, stromal cells secrete factors, cause T cell upregulation of CCR4, CCR10, PSGL-1.
3) T cells migrate to skin
Metabolites that imprint on lymph nodes gut addressins
Vitamin A metabolites
What causes T cells to differentiate into Th1? 1) 2) 3) 4) 5)
1) Dendritic cell presents antigen to naive T cell on MHCII
2) DC or macrophage releases IL-12
3) NK cell releases IFNg
4) IL-12 activates STAT4 transcription factor
5) IFNg activates STAT1, T-bet transcription factors
How does Th1 amplification occur?
Th1 releases IFNg, autostimulates
What do STAT1, STAT4 and T-bet do?
Transcription factors activated by IL-12 and IFNg
Lead to Th1 phenotype
Th1 functions 1) 2) 3) 4) 5) 6)
1) Macrophage activation
2) Infected cell killing
3) T cell proliferation
4) Differentiation in bone marrow
5) Endothelial activation
6) Chemotactic effects
With what do Th1 activate macrophages?
IFNg, CD40L
With what do Th1 kill cells?
FasL, LTbeta
With what do Th1 induce T cell proliferation?
IL-2
With what do Th1 induce differentiation in the bone marrow?
IL-3, GM-CSF
With what do Th1 induce endothelial activation?
TNFa, LTalpha
With what do Th1 induce chemotaxis?
CXCL2
How do naive T cells differentiate into Th2? 1) 2) 3) 4)
1) DC presents antigen to T cell
2) Mast cells (maybe eosinophils) release IL-4
3) IL-4 activates STAT6. Unknown factor activates GATA3
4) Th2 releases IL-4, autostimulates
Activated Th2 effects 1) 2) 3) 4)
1) IL-4 biases antibody isotype to IgG, IgE. IgE leads to sensitisation of mast cells
2) IL-4, IL-13 lead to intestinal mucosal secretion, peristalsis
3) IL-5 activates eosinophils
4) IL-4, IL-13 lead to alternative macrophage activation
Roles of alternative macrophages
Enhanced fibrosis and tissue repair
Transcription factors leading to Th2 phenotype
STAT6, GATA3
How are naive T cells biased towards Th17? 1) 2) 3) 4)
1) DC presents antigen, releases IL-1, IL-6. TGFb from other sources
2) IL-6 activates STAT3. TGFb activates RORgammaT.
3) IL-21 is released for autostimulation
4) DC releases IL-23. Th17 is mature
Role of IL-17
1)
2)
1) Causes leukocytes and tissue cells to release TNFa, colony stimulating factors, chemokines, IL-1 and IL-6
2) This leads to inflammation, neutrophil response, antimicrobial peptides
Effect of IL-23
1)
2)
1) Increases barrier function of epithelial cells
2) Increase in antimicrobial peptides
Factors released by Th17
1)
2)
3)
1) IL-17
2) IL-22
3) IL-23
Basic CD8+ killing 1) 2) 3) 4)
1) Non-specific attachment
2) Specific recognition
3) Cytoskeletal changes
4) Granule release
Perforin
1)
2)
1) Pore-forming enzyme
2) Aids delivery of granzymes and granulysin into target cell
Granzyme
1)
2)
1) Family of serine proteases
2) Induces apoptosis in target cell
What is serglycin?
Forms a complex with perforin and granzymes
How do CD8+ granules kill target cell? 1) 2) 3) 4) 5) 6)
1) Complex of serglycin, granzyme and perforin is released by CD8+ T cell
2) Perforin forms pore, granzyme enters host cell
3) Granzyme B activates pro-caspase 3, BID
4) Truncated BID activates BAX and BAD on mitochondrial surface, disrupts mitochondria. Caspase 3 activates DNAases
5) Cytochrome C released from mitochondria. Causes apoptosis
6) DNAases induce DNA fragmentation
What forms a complex with granzyme and perforin?
Serglycin
Fas/FasL pathway 1) 2) 3) 4)
For apoptosis of target cell
1) FasL binds Fas on target cell, causing Fas to trimerise.
2) ‘Death domain’ (intracellular) of Fas recruits FADD, with death effector domain (DED)
3) DED recruits pro-caspase 8
4) Pro-caspase 8 accumulation leads to activation, apoptosis
What plays a major role in eliminating unwanted T cells?
Death via the Fas/FasL pathway
What do mutations in the Fas/FasL pathway lead to?
Autoimmune lymphoproliferative disease
What causes autoimmune lymphoproliferative disease?
Mutations in the Fas/FasL pathway
Where do CD4 and CD8 T cells sit with regards to site of infection?
CD8+ sit next to infected cells
CD4+ sit further away from site of infection
What can activate Th IFNg release?
Only professional APCs
