Lecture 7 - Effector CD4 T cells Flashcards
What is a ‘primed’ effector cell?
cell that is getting ready to respond
What is a ‘effector’ cell?
cell that has been induced to differentiate into a form and ready to function
What is the process of T cell activation?
1) Niave T cells differentiate into ‘primed’ effector T cell when interact with APC presenting peptide/MHC complex, CD28 with CD80/CD86 - signal the T cell to get ready to be activated
2) Rearrangement of the cytoskeleton leads to concentration of key molecules required for activation creating a central ‘cap’ - immunological synapse
3) The IS tells T cells to become activated through the recruitment of kinases. Signal i (MHC/peptide complex) and signal 2 (costimulation CD28 and CD80/CD86) triggers phosphorylation of TCR receptors, changes protein from inactive to active
4) IL-2 growth hormone produced
When is IL-2 produced?
1) T cells activated
2) when T cell binds to APC releases small amopunt of IL-2, needs larger signal to survive and proliferate
- uses feedback loop to initiate proliferation and expansion of T cell
Where does priming take place and how long does it take?
Priming takes place in the lymph nodes and take 2-3 days
What is the importance of differentiation of activated primed T cells?
To supply the best immune response to deal with the type of threat presented e.g. parasites need IgE
Which signal governs differentiation in T cells?
Signal 3
- surface molecules CD40
- cytokines
What are cytokines?
- small proteins (hormones) that allow communication between immune and non-immune cells
- widespread thoughout body
- act locally between APC and T cell
- bind to specific receptors
What are two subclasses of cytokines?
- Interleukins (IL) e.g. IL-2, IL-4
- Interferons (IFN) e.g. IFNy
What are the four types of effector CD4 T cells and what cytokines are they characterised by?
-Th1 (T helper 1) interferon gamma (IFNy)
-Th2 (T helper 2) interleukin… (IL-4, IL-5, IL-13)
-Th17 (T helper 17) interleukin 17 (IL-17)
Treg (Regulatory T)transforming growth factor beta (TGFb) interleukin 10 (IL-10)
What are features of the four types of effector CD4 T cells?
- each T cell cannot produce the cytokines other T cells produce
- cannot undifferentiate T cells into different type
What are the functions of cytokines?
1) induce differentiation of an activated CD4 T cell into correct subtype
2) Differentiated T cell subtype produces cytokines to deal with pathogenic threat
TO
-enable macrophages to destroy intracellular bacteria
-enable B cells to transform into plasma cells and secrete antibodies
How do cytokines induce differentiation of activated CD4 T cells into appropriate sub type?
cytokines can control what TF/promoter combination are brought together
1) Th1 production of IFNy controlled by TF T-bet binds to IFNy promotor upstream of the IFNy gene
2) Th2 production of IL-4 controlled by TF GATA-3 binding to IL-4 promoter upstream of IL-4 gene
3) Th17 production of IL-17 controlled by TF RoRyT binding to promoter upstream of IL-17 gene
What cytokines are produced by APC to induce the appropraite TF for each type of T CD4 cell?
1) Th1 = IL-12 induces T-bet
2)Th2 = IL-4 induces GATA-3 (feedback loop)
3) Th17 = TGFb and IL-6 induce RoRyT
4) Treg TGFb and IL-2 induce Foxp3
cytokines that T cell recieves determine which TF is activated and which subset differentiate in to
How cytokines induce transcription
1) cytokine receptors are not in active form
2) binding of cytokine to receptor causes change in cytokine intracellular region, recruits kinases
3) kinases phosphorylate cytokine receptor which activates signal-transducing activator or transcription (STAT)
4) STAT interacts with and transports the transcription factors to the promotor
5) induces cytokine production
What is the specific process of activation for a Th1 cell?
1) Cytokine IL-12 (from APC) binds to IL-12 receptor and triggers phosphorylation by recruitment of kinases
2) IL-12 receptor triggers activation of STAT 4
3) STAT 4 seeks out and binds transcription factor T-bet
4) T-bet binds to IFNy promoter and induced IFNy production
5) results in positive feedback
What is the specific process of activation for a Th2 cell?
1) Cytokine IL-4 (from APC) binds to IL-4 receptor and triggers phosphorylation by recruitment of kinases
2) IL-4 receptor triggers activation of STAT 6
3) STAT6 seeks out and binds transcription factor GATA-3
4) GATA-3 binds to IL-4 promoter and induces IL-4 production
5) results in positive feedback
What are people deficient in CD8 cells prone to?
Viral infection
What are people deficient in B cells prone to?
Bacterial infection
What are people deficient in CD4 cells prone to?
Susceptible to almost everything as CD4 acticate many arms of immune response
What is the dominant antibody response of Th1 cell?
IgG2a, IgG3
What pathogens do Th1 cells tackle?
intracellular bacteria and protozoa by IFNy acticating macrophage infected to kill off e.g. Mycobacterium, Toxoplama gondii, Leishmania major, Trypanosoma cruzi
What is the dominant antibody response of Th2 cells?
IgG1, IgGE
What do Th2 cells tackle and how?
IL-4 and IL-5 induce B ccells to become plasma cells and secrete antibodies specific for dealing with extracellular pathogens/helminths e.g. Schistosoma mansoni, Trichuris muris (parasitic worm)
How do IFNy help macrophages?
1) Th1 cell returns to site of infection and binds to infected macrophage via peptide MHC molecules
2) Whilst the macrophage is infected with bacteria it degrade the proteins to peptides and presents bacterial peptides in MHCII complexes
3) IFNy binds to IFNy receptor on macrophage and triggers a range of effects
What are the effects of IFNy binding to IFNy receptor on macrophage?
a) upregulated the ability of macrophages to degrade bacterial proteins present on surface of the cell in MHCII complexes b) allowing macrophage to increase surface moleules and costimulatory molecules making it more attractive to other CD4 cells c) multiple binding sites lead to an influx of IFNy into macrophages which activates macrophages d) triggers the production of nitric oxide and reactive oxygen intermediates destruct bacterial cell wall and die
How do effector Th2 cells help B cell activation? (for dealing with worm infection)
1) Antigen recognition induces expression of effector molecules by T cell (IL-4, IL-5, IL-6) activating B cell
2) Leads to b cell proliferation
3) differentiation to resting memory cells and antibody secreting plasma cells
4) CD4 T cell help dictates antibody class switch decision - expresses cytokines tell B cell to stop producing IgM and start producing IgG1 or IgG2A or IgA or IgE
What do T helper 17 cells result from?
the differentiation of an activated CD4 T cell exposed to transforming factor B (TGFB) and IL-6
What do T helper 17 cells produce?
IL-17 following binding of RoRyT TF to IL-17 promoter
What is the immune role of T helper 17 cells?
unclear
- links to autoimmunity (people with autoimmune disorders have a lot of Th17 in damaged organ)
- may protect gut against pathogens
- involved in neutrophil recruitment
Where do CD4 Tregs develop?
develop naturally in the thymus or can be induced by exposure of activated CD4 T cells to IL-2 and TGF-b (adapted Treg cell)
What are the different subtypes of Tregs?
FoxP3 and Treg cells
What is Fox p3?
a TF induced by TGFb and IL-2
What are Treg cells important for?
- switching off autoreactive T cells
- produce cytokines to kill
- contains large amount of negative costimulator molecules on surface and can give negative signal to autoreactive T cells, capable of killing them
