Lecture 9 - T-cell mediated responses I Flashcards
Mounting an appropriate immune response: what is needed and what causes this to happen?
For immunity - an appropriate and adequate pathogen-specific must occur
This is largely achieved by cytokines cause CD4+ T-cell activation which allows for a pathogen-specific response
Naive CD4+ T-cells: what are the types and how do they differ?
Circulatory T-cells are inactivated, once activated they differentiate
Th1 - intracellular pathogens
Th2 - extracellular pathogens
Th17 - Fungal and extracellular bacterial pathogens
Tfh (follicular helper) - promotes b-cell activation
Th9 - anti-parasite, anti-tumour immunity, auto-immunity, and triggering allergic inflammation (may not be an actual subset? ER)
Tregs - control immune responses (prevents extreme immune responses)
T-cell nomenclature: why is it so strange?
Named after the interleukin they produce
What three signals are required for T-cell activation
- T-cell-antigen recognition (MHCII)
- Co-stimulatory molecule binding
- Cytokines
Cytokines: where can they come from?
- Dendritic cells
- Innate lymphoid cells
- Mast cells
- Macrophages
- Epithelial cells
IL-2: what is it and what does it do?
Growth factor for T-cells through STAT5 signalling - acts in an autocrine/paracrine manner for the T-cells themselves - prevents them from dying, promotes CD8+ T-cell activity
STAT: what is it, what does it do, and what are some examples?
Signal transducer of activation
Family of transcription factors that determine the differentiation of T-cells
- STAT1 - along with STAT4 it promotes T-bet expression
- STAT2 - ? (ER)
- STAT3 - promotes RORα/γt expression, promotes Tfh differentiation (differentiated by cytokines promoting the pathway)
- STAT4 - along with STAT1 it promotes T-bet expression
- STAT5 - induces proliferation
- STAT6 - promotes GATA3 expression
Epigenetics: what is it and what is an example?
Any change that modifies gene activity without altering the base DNA sequence
DNA methylation in promoter region or gene regulatory region leads to making gene more or less accessible for transcription
Epigenetics: how may it affect T-cells?
Methylation of DNA may occur causing genes to be ‘locked’ and preventing certain types of differentiation
DNA methylation: what is it, is it heritable, and what is it regulated by?
Methylation of DNA - may result in gene expression being more/less accessible for transcription
Yes, from the mother cell to the daughter cell so any methylation will pass down to populations formed after division
Methylation patterns regulated by DNA methyl transferases
Th1 cells: what pathogens do they detect, how is the differentiation into it achieved, what other cytokines are they affected by, and what is the Th1 specific transcription factor?
Intracellular pathogens - virus, intracellular bacteria, etc
Signal 3 pathways (more specifically the bottom two) result in the stabilisation of T-bet:
* IL-27 and IFN-γ causes STAT1 pathway activation
* IL-12 causing STAT4 pathway activation
IL-2 induces proliferation through the STAT5 pathway
Th1 specific transcription factor - T-bet, cytokines encouraging an immune response - IFN-γ
T-bet: what is it, what does it do, what is it activated by, and what cytokines are produced through its activation?
T-box expressed in T cells - a transcription factor
Promotes differentiation into Th1 cells
- STAT1 pathway through IL-27 and IFN-γ
- STAT4 pathway through IL-12
Th1 cells produce:
- INF-γ (positive feedback)
- IL-2 (positive feedback)
- TNF-α
- TNF-β
Transcription factors: what are they?
Proteins within the body that regulate gene transcription
Th2 cells: what pathogens do they detect, how is the differentiation into it achieved, what other cytokines are they affected by, and what is the Th2 specific transcription factor?
Extracellular pathogens - helminth parasitic worms, etc
Signal 3 pathways result in the stabilisation of GATA3:
* IL-4 induces proliferation via STAT6 signalling
IL-2 induces proliferation through the STAT5 pathway
GATA3
GATA3: what is it, what does it do, what is it activated by, and what molecules are produced through its activation?
Guanine-adenine-thymine-adenine (GATA) binding protein 3
Detect GATA sequences and bind, promoting gene expression - promotes T-cell differentiation into Th2 cells
IL-2 through the STAT5 pathway and IL-4 through STAT6 signalling
- IL-13 - promotes effects that defend against extracellular parasites
- IL-4 along with IL-13 promotes M2-like macrophage differentiation (also positive feedback)
- IL-5 - eosinophil recruitment and activation
- IL-3 and IL-9 - promoting and activating mast cells
IL-13: what is it produced by and what does it do?
Th2 cells
- Promotes effects that defend against extracellular parasites - epithelial cell repair, mucus production, smooth muscle contraction (epithelial cell layer is becoming less hospitable)
- (Along with IL-4) promotes M2-like macrophage differentiation
IFN-γ
Activates macrophages and cytotoxic T-cells
Th1 cell positive feedback
- INF-γ drives regulation of T-bet
- T-bet causes INF-γ and IL-12R production, resulting in an autocrine and paracrine positive feedback loop
Th2 cell positive feedback
- IL-4 causes GATA3 expression
- GATA3 causes IL-4 production
Th cross inhibition: what is it and how does it occur?
- T-bet inhibits GATA3
- GATA3 inhibits T-bet
This occurs through epigenetic markers which prevent expression (ER?)
Th1 vs Th2 helper cells: what do they detect, what is their master transcription factor, and what do they do?
Th1:
* Intracellular pathogens
* T-bet
* Activate cell-mediated immunity (macrophages CD8+ cytotoxic T-cells)
Th2:
* Extracellular pathogens - parasites
* GATA3
* Promotes tissue repair and granulocyte recruitment and activation
Th17 cells: what pathogens do they detect, how is the differentiation into it achieved, are there any cytokines that inhibit them, and what are the Th2 specific transcription factors?
Deal with fungal and extracellular bacterial pathogens (also associated with several autoimmune diseases)
Signal 3:
* STAT3 signalling through IL-6
* Smad signalling through TGF-β
* IL-1β
* IL-21
* IL-23
IL-2
RORα and ROR-γT
Th17 cells: what is their positive feedback loop?
Not present like within Th1 and Th2 cells
Instead, Th17 relies on accessory cells releasing the cytokines:
* IL-1β
* IL-21
* IL-23
RORα and ROR-γT: what are they, what do they do, what are they activated by, what other cytokines are they affected by, and what molecules are produced through their activation?
Retinoic acid receptor (RAR)-related orphan receptor α and RAR-related orphan receptorγt
Cause Th17 cell differentiation, results in recruitment of neutrophils (IL17 results in stromal CXCL2 production, the main neutrophil recruitment factor) and also results in anti-microbial protein induction (RegIIIγ, RegIIβ, S100A8, and S100A9)
- STAT3 signalling through IL-6
- Smad signalling through TGF-β
IL-2 - inhibited by it, unlike with Th1/2
IL-17A
IL-17F
S100A8 and S100A9: what are they, what are they produced by, and what do they do?
Calgranulin A and calcium-binding protein A9
Induced by IL-17
Anti-microbial proteins - sequester calcium in the environment to reduce Ca²⁺ supply for the proliferating microorganism
Monogenic disorders: what are they, what is an example, what mutations occur in this example, and what is the result of the example?
Diseases caused by a single mutated gene
Job syndrome
STAT3 mutations
Results in Th17 deficiency
Tfh: what are they, what does it needs for its activation, what types are there, and what do they do?
Follicular T helper cells - promotes B-cell responses
Signal 3:
* IL-6 via STAT3 signalling
* IL-21 via STAT3 signalling
Different dependent on immune response required: Tfh1, Tfh2, Th17, etc
- Promotes Bcl-6 expression - inhibits BLIMP-1
- Expresses CXCR5 - chemokine allowing T-cells to move to B-cells
- Produces IL-21 key cells in promoting B-cells germinal response
Tfh1 cells: what are they, what do they produce, and what is their master transcription factor?
Tfh cells with similar phenotypes to Th1 cells - act to support the Th1 response to intracellular infections
- IFN-γ
- IL-21
- IgG2a
- IgG2c
T-bet
Tfh2 cells: what are they, what do they produce, and what is their master transcription factor?
Tfh cells with similar phenotypes to Th2 cells - act to support the Th2 response to extracellular parasites
- IL-21
- IL-4
- IL-13
- IgE
GATA3
IgE - mast cells, large pathogens in GI tract
Tfh17 cells: what are they, what do they produce, and what is their master transcription factor?
Tfh cells with similar phenotypes to Th17 cells - act to support the Th17 response to extracellular parasites
- IL-17
- IL-21
- IgG2a
- IgG3
RORα/γt
Tfr cells: what are they, what do they do, what is their master transcription factor: and what do they produce?
T follicular regulatory cells
Inhibit immune activation - regulation
Foxp3
CTLA-4
Foxp3: what is it, what does it do, what is it activated by, and what molecules are produced through its activation?
Forkhead box P3 protein
Regulate immune responses
TGFβ
CTLA-4
IL-1β: what does it do and what Th cells is it associated with?
Promotes Th17 differentiation and expansion
Th17 cells
IL-2: what does it do and what Th cells is it associated with?
Causes STAT5 pathway activation - proliferation and survival of T-cells
Th1 and Th2 cells
IL-3: what does it do and what Th cells is it associated with?
Promotes mast cells
Th2 cells
IL-4: what does it do and what Th cells is it associated with?
Promotes differentiation into Th2 cells via the STAT6 pathway - stabilising GATA3
Promotes M2-like macrophage differentiation along with IL-13 and promotes tissue repair
Th2 cells, Tfh2 cells
IL-5: what does it do and what Th cells is it associated with?
Eosinophil recruitment and activation
Th2 cells
IL-6: what does it do and what Th cells is it associated with?
Activates the STAT3 signalling pathway, results in activation of ROR-αand RORγt TFs
Th17 cells, Tfh cells
IL-9: what does it do and what Th cells is it associated with?
Promotes mast cell
Th2 cells
IL-12: what does it do and what Th cells is it associated with?
Encourages Th1 differentiation through the STAT4 pathway - stabilising T-bet
Th1 cells
IL-13: what does it do and what Th cells is it associated with?
Promotes epithelial cell repair, mucus production, and smooth muscle contracting
Th2 cells, Tfh2 cells
IL-17: what does it do, what types are there, and what Th cells is it associated with?
Results in the recruitment of neutrophils through CXCL2 receptor expression, the main neutrophil recruitment factor and also induce anti-microbial gene expression
- IL17A
- IL17F
Th17 and Tfh17 cells
IL-21: what does it do and what Th cells is it associated with?
- Promotes Th17 differentiation and expansion
- Activates the STAT3 pathway, activating Tfh cells
Th17 cells and Tfh1/2/17 cells
IL-23: what does it do and what Th cells is it associated with?
Promotes Th17 differentiation and expansion
Th17 cells
IL-27: what does it do and what Th cells is it associated with?
Causes STAT1 pathway activation along with IFN-γ - differentiation into Th1 cells stabilising T-bet
Th27 cells
IFN-γ: what does it do and what Th cells is it associated with?
Causes STAT1 pathway activation along with IL-27 - differentiation into Th1 cells by stabilising T-bet
Th1 cells, Tfh1 cells
TGF-β: what does it do and what Th cells is it associated with?
Causes Smad signalling pathway activation, resulting in activation of ROR-αand RORγt TFs
Th17 cells
Bcl-6: what does it do and what Th cells is it associated with?
Key transcription factor associated with being a Tfh cell, inhibits BLIMP-1 expression
Tfh cells
CXCR5: what does it do and what Th cells is it associated with?
Chemokine allowing T-cells to move to B-cells
Tfh cells
IgG2a: what does it do and what Th cells is it associated with?
Antibody that is used to clear viral infections
Tfh1 cells
IgG2c: what does it do and what Th cells is it associated with?
Antibody that is used to clear viral infections
Tfh1 cells
IgG3: what does it do and what Th cells is it associated with?
Various effector functions against all pathogens
Tfh17 cells
IgE: what does it do and what Th cells is it associated with?
Antibody that results in mast cell activation and clearing of pathogens in the GI tract
Tfh2 cells
CTLA-4: what does it do and what Th cells is it associated with?
Cytotoxic T-lymphocyte antigen 4 - key Treg cytokine
Tfr cells
