T cell signalling in activation and disease Flashcards
what 3 types of interaction are required to activate T cells
TCR interaction with MHC
Co-stimulation
cytokine stimulation
which 2 src family tyrosine kinases are involved in t cell signalling upon binding to MHC
Fyn and LcK
describe the structures of Fyn and LcK tyrosine kinases involved in T cell signalling
they consist of a catalytic domain Y, and SH3 domain which interacts with polypro line motifs and an SH2 domain which recognises phosphorylated erosion residues
How are Fyn and LcK activated
dephosphorylation by CD45 stimulated by MHC recognition
How are CD4/CD8 involved in TCR/MHC signalling
stabilise the interaction between the invariant regions of MHC and TCR. They also help to recruit src kinases to the TCR complex to allow signalling
describe the signalling pathway which results from TCR binding MHC
Fyn and LcK are dephosphorylated and activated by CD45. These then phosphorylate tyrosine residues on the CD3 regions of the TCR complex which contain ITAMs. Phosphorylated regions can then act as docking ports for other essential proteins such as Zap70 which binds via SH2 domains. This is phosphorylated and activated. Zap70 then phosphorylates LAT. This is an adaptor protein which becomes activated and recruits proteins which are able to dock via SH2 domains. Grab 2 binds LAT via its SH2 domain and also binds SOS via its SH3 domain. This then activates Ras gtpase leading to downstream MAPK signalling resulting in cell proliferation.
LAT also binds SLP76 which is phosphorylated by ZAP70. this results in cytoskeletal rearrangement. Finally Phospholipase C cleaves PIP2 to form DAG and IP3. DAG activates PKC and IP3 mobilises intracellular calcium stores from ER to increase calcium dependent signalling which is required for T cell activation
what is the role of lipid rafts in TCR signalling
all signalling proteins are either permanent or temporary members of lipid rafts
why is it important that CD45 is only a temporary resident of lipid rafts
because it begins signalling by dephosphorylating Fyn and LcK however subsequent signalling is reliant upon phosphorylation and so it must be quickly removed to prevent it dephosphorylating proteins found further in the signalling cascade.
describe the CD28 co stimulation signalling cascade
CD28 binds B7 on APcs. PI3K binds CD28 via its SH2 domain which then phosphorylates PIP2 to PIP3. This recruits her proteins to the site of activation e.g. PLC and protein kinase B.
what is the importance of the CD28 co stimulation
it is a cell survival pathway and controls energy demand in the T cell helping the cell to cope with energy demands from growing and proliferating. It also changes the dynamics of signalling from the TCR, potentiating TCR-mediated MAPK signalling and IL2 transcription
What is the role of the Th polarising signal from DCs
it tells naive T cells what to differentiate into. The polarising signal is dependant upon Dc polarisation which comes from pathogens and the extracellular millieu to drive appropriate development of Th cells
describe the signalling pathway which results from Th1 polarising signals from the dendritic cell
DC releases IL 12 which recruits NK cells. These produce IFNg which binds to a receptor on the naive T cell and activates the STAT1 transcription factor. STAT1 travels to the nucleus and switches on a number of genes including T-bet which promotes gene expression of another transcription factor which then binds the promoter of IFNg gene, resulting in IFNg expression. This then acts in an autocrine manner. T-bet also causes up regulation of the IL12 receptor, increasing the T cells responsiveness to IL12 signals from DC cells. Il12 activates STAT4 transcription factor which also binds the T-bet promoter, reinforcing IFNg production and Th1 polarisation in order to fight intracellular pathogens
describe the signalling pathway which results from Th2 polarising signals from the dendritic cell
DC cells bind to TCR and activate the GATA3 transcription factor which binds to promoters of IL4, Il5 and IL13 genes. these are hallmark cytokines of TH2. it also up regulates IL2 expression for cell proliferation. DC binding also results in signalling through the Notch pathway which again causes transcription of IL4,5 and 13. Finally, basophils produce IL4 which binds to the IL4R on T cells, activating STAt6 which, again, promotes transcription of Il4,5 and 13 creating an autocrine loop.
what can be the result of innappropriate T cell signalling
oncogenesis
