CD4+ T Cell Responses Flashcards
What is signal 3 in the T cell response?
- Signal 1 → antigen recognition by CD4+ T cell in the context of MHC
- Signal 2 → co-stimulatory molecules (eg CD28-CD80/86). This interaction is strengthened by adhesion receptors, eg) LFA-1/ICAM-1 interaction.
− Co-stim molecules upregulated on APCs in response to pathogens - Signal 3 → cytokine signal to promote differentiation into CD4+ T cell subsets
− Can come from the DC
− Can come from other accessory immune cells
• As well as cytokines to promote differentiation, IL-2 is required to drive T cell proliferation
• Signal 3 triggers intracellular differentiation signals via STAT signaling:
− The receptor is activated by a signal from an IFN, interleukin, growth factor or other chemical messenger
− This activates the JAK, which autophosporylates itself
− The STAT protein then binds to the phosphorylated receptor, where STAT is phosphorylated by JAK
− STAT binds to another STAT, and translocates to the nucleus
− STAT signaling promotes the expression of CD4+ subset-specific TFs
• You also get epigenetic changes occurring in the cells:
− Important for the differentiation changes to be heritable when the T cell divides
− Epigenetic means ‘in addition to changes in genetic sequence’
− Methylation by methyl transferases is the classical epigenetic change – methylation patterns are heritable from cell to cell.
→ epigenetic changes have been noted in diseases such as Grave’s disease and biliary atresia.
What are the Th1 characteristics?
• IL-2 induces proliferation via STAT-5 → signal 2
• Signal 3 → IFNy and IL-27 responsible for differentiation – signal via STAT1
• IL-12 secreted from DCs acts via STAT4
• Signalling promotes expression of the TF T-bet → T-bet works with STAT1 triggered by IFN-y and STAT4 activated by IL-12 to promote full Th1 differentiation
• IFN-y is produced by the TH1 cell → reinforces signal 3
• Differentiated Th1 produces
− IFN-y → classical Th1 cytokine
− IL-2
− TNF-a
− TGF-b
• Essential in responses to intracellular pathogens
− Interact with macrophages presenting antigen → IFNy promotes further activation of macrophages
− Stimulates CD8+ T cells promoted via IL-2 and IFN-y
− Also stimulates B cells to produce opsonizing antibodies
What are the Th2 characteristics?
• IL-2 as signal 2
• Signal 3 → IL-4 signals via STAT6 to promote differentiation
• Signalling stabilizes the TF GATA3 → Gata3 causes phosphorylation of STAT6 under IL-4 stimulation to control Th2 differentiation
• Co-transcription factor Dec2 induces Gata3 expression and Dec2 deficiency leads to impaired Th2 responses
• Differentiated Th2 produce:
− IL-4 → classical. Reinforces Th2 signal
− IL-5
− IL-13
• Essential in responses to extracellular pathogens
− Causes class-switching to induce neutralizing IgE production → activates mast cells basophils, eosinophils
− Activate and recruit granulocytes directly via Th2 cytokines, and indirectly via IgE
What is the cross-talk between Th1 and Th2 cells?
Positive feedback loops re-inforce differentiation:
• Th1
− IFNy (from eg, NK cells) helps drive Th1 upregulation via T-bet
− IFNy produced by Th1 cells feedback
− T-bet drives expression of the IL-12 receptor – IL-12 promotes T-bet
• Th2
− IL-4 (from eg, basophils) helps drive upregulation of Gata3
− IL-4 produced by Th2 cells feedback
Cross-inhibition of Th1-Th2 differentiation
• Th1 cells down-regulate production of Th2 cells by secretion of IFN-y. T-bet inhibits expression of Gata-3
• Th2 cells down-regulate production of Th1 cells by secretion of IL-4. Gata-3 inhibits expression of T-bet
What are the characteristics of Th17 cells
Differentiation:
• IL-2 is inhibitory for Th17
• Signal 3 → TGF-B via Smads and IL-6 via STAT3 to promote differentiation
− You need these in combination, TGF-b alone gives a different outcome
− Need pro-inflammatory IL-6
• These promote the expression of the TF RORa and RORyt
• IL-1B, IL-21 and IL-23 also help promote and stabilize Th17 differentiation and expansion
• Differentiated Th-17 produce:
− IL-17A → classical
− IL-17F → classical
− IL-21
Function:
• Deal with fungal and extracellular bacterial pathgoens
• Key cells in several autoimmune idseases
− Inflammatory bowel disease
− Rheumatoid arthritis
− Type 1 diabetes
− Multiple sclerosis
− Also airway hypersensitivity in allergic asthma
• IL-17 modulates immune responses by inducing expression of immunomodulatory molecules
− Recruitment/activation of immune cells via induction of chemokines
− Anti-microbial protein production eg) defensins
egs)
• IL-17 is overexpressed by inflamed lung endothelial cells, rheumatoid arthritis and SLE patient serum samples.
• IL-17 also associated with skin inflammation
• IL-17 neutralising antibodies could have the potential to treat autoimmune disease
• IL-23 involved in maintenance of Th17 cells promotes inflammation in Crohns disease
• Th17 cells also have a potential role in cancer:
− In murine melanoma models, adoptive transfer for Th17 cells induced complete and lasting tumour regression, and was IFNy dependent.
What are the characteristics of Tfh Cells
Differentiation:
• Signal 3 → IL-6 and IL-21 via STAT3 signalling
• These promote the expression of Bcl-6, which inhibits the expression of BLIMP-1
• Full differentiaton requires interaction with activated B cell presenting specific antigen
• Differentiated Tfh cells produce:
− IL-4 → important for antibody production
− IL-21 → reinforces IL-4
Function:
• Promote B cell responses
• Key cells in germinal centre formation
− Promotes B cells to stay in the germinal centres via induction of Bcl-6 in the B cell → promotes maintenance and somatic hypermutation
− Promotes proliferation of B cells via IL-4 and IL-21
− Promote plasma cell differentiaton → IL-21 plus addition IL-6 and IL-10 lead to upregulation of BLIMP-1 in the B cell
− Can also promote formation of memory B cells
− Also important for inducing apoptosis of the germinal centre in certain situations via the Fas pathway.
What are the characteristics of Th9 cells
Differentiation
• IL-2 promotes proliferation via STAT5
• Signal 3 → TGF-B via Smads and IL-4 via STAT6
• Promote the expression of IRF-4 which promotes the expression of PU-1
• Differentiated Th9 produced iL-9
Function
• Important in nematode worm expulsion
• IL-9 induces a mast cell response
What are the characteristics of Tr1 cells?
- CD4+ Foxp3-
- Produced by IL-10 stimulation
- Suppress immune responses by production of IL-10 and TGF-B
What are the characteristics of Th3 Cells
- CD4+ Foxp3-
* Produce large amounts of TGF-B
What is the evidence that Foxp3 marks Tregs?
- “Disruption of a new forkhead/winged helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse” → Brunkow et al
- “The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome is caused by mutations of Foxp3” – Bonnett et al,
- Specific disruption of Foxp3 gene results in lethal inflammation in mice
- Expression of Foxp3 in CD4 T cell is sufficient to turn it into a Treg
What are the characteristics of nTregs?
• Develop in the thymus as part of normal T cell development
Model:
• Believed that in the thymus there is a ‘precursor’ → CD4+ Foxp3- CD25-
• If you get strong engagement of the TCR, you get upregulation of CD25 → CD4+ Foxp3- CD25+
• Increased IL-2, increased costimulatory CD28 and increased NFkB → CD4+ Foxp3+ CD25+
• Dogma has always been that Tregs are induced when TCRs are reactive against self-antigen, however this is controversial.
What are the characteristics of iTregs?
- Most prominent in the gut, induced via specialsed DCs → CD103+
- avb8 expressed on DCs is critically important for maintaining immune homeostatsis → mice lacking avb8 on DCs develop autoimmune colitis
- Lack of avb8 on DCs also characterized by a reduced population of T regs in the intestine (Travis et al, 2007)
- Lack of avb8 is associated with reduced TGF-b activity → highly suggests activation of TGF-B by avb8 on DCs is crucial for inducing Tregs in the intestine.
- These can be induced during certain infections → counter-intuitive, but they help modulate the immune response to stop an overt inflammatory response.
- Parasitic infections upregulate the Treg response to help them become chronic
- Ever since the recognition of iTregs, three has been a focus on identifying phenotypic markers that can distinguish them from Tregs
- No definitive ones, but suggested → Helios+ nTregs, Helios- iTregs (Tran et al, 2010)
How do T regs suppress?
Cytokine Dependent
• Initial in vitro assays suggested not important, but later in vivo assays suggested TGF-B and IL-10 are key in Treg mediated suppression
Induction of T cell Death
• Tregs secrete perforin and granzyme
Disruption of T cell Effector Mechanisms
• Tregs mop up IL-2 so it cant be used by effector T cells for proliferation and differentiation
• CD25 is part of the IL-2 receptor → gets upregulated on Tregs upon activation
• Tregs also produce adenosine that inactivates lymphocytes
Targeting of DCs
• CTLA-4 is expressed on Tregs and activated T cells
• Binds with high affinity to CD80 and 86
• Downregulates their expression
• Tregs also block T cell acess to DCs → if Foxp3+ Tregs bind with a higher affinity to the antigen, T cells cant bind
− Suggested that Tregs are more enriched to recognize antigen than normal effector T cells
What is meant by CD4+ plasticity?
- First descriptions of Th1 and Th2 cells stated that cross-inhibtion occurred, with T-bet repressing Gata3 and vice versa
- Now believed it isn’t so simple!
eg)
• Foxp3+ Tregs can be converted to Th17 cells (RORyt and RORa) or Tfh cells (Bcl-6)
• Can also get ‘hybrid’ T cell subsets eg)
− Th1/17 cells → expressing T-bet and RORyt → secreting IFNy and IL-17
− Th1/2 cells → expressing Tbet and Gata3 → secreting IFNy and IL-4
• Not really known why, but could be to do with co-infections!
What is meant by CD4+ T cell migration?
• After activation, need to migrate to focus of infection
• For Th1 cells → CCR5 will lead them into inflamed tissue
• S1P receptors are GPCRs that are key in driving naïve CD4 T cells out of the thymus into secondary lymph nodes after their maturation
• During activation, S1P receptors are downregulated to keep the T cell in the lymph node
• After this, S1P is re-expressed along with Klf2, driving effector T cells into inflamed tiussues
• ECM1 is responsible for S1P and Klf2 revival in Th2 cells through interaction with IL-2 receptor
− Shows that Th2 cells are under control of IL-2 signals not only in early differentiation, but also in late activation.
