Lecture 7 T cells Flashcards
How do T cells develop?
Develop in the bone marrow and complete their development in the thymus independent of antigens. T cells undergo selection- strongly self reactive T cells are eliminated in the thymus through apoptosis. Thymocytes mature into either CD4 or CD8 naive T cells.
What happens to developed T cells?
Leave the thymus to recirculate until they meet their specific antigen. Naive CD4 T cells can recognise MHC class II and CD8 T cells can recognise MHC class I. Naive T cells divide infrequently and can live for many years.
What do T cells encounter in the periphery?
Their specific antigen (T cell priming). They are induced to proliferate and differentiate (clonal expansion) into cells capable of removing antigen: armed effector T cells and memory T cells. This takes several days.
What do CD8 T cells differentiate into?
Cytotoxic T cells.
What do CD4 T cells differentiate into?
TH1 cells, TH2 cells, TH17, T reg cells
Why do T cells need to sample immunogenic peptides presented to them via the MHC molecules?
To differentiate into a specific type of effector cell. Dependent on the abundance of antigen presenting cells and T cells. Increasingly rare event that two cells where one presents the right antigen and the one that has the fitting receptor meet. These encounters are facilitated by bringing the T cells and their antigens in close proximity.
What are the steps to activating naive T cells?
T cells enter lymph node across high endothelial venules in the cortex. T cells monitor antigen presented by macrophages and dendritic cells. T cells that do not encounter specific antigen leave lymph node through lymphatics. T cells that encounter specific antigen proliferate and start to differentiate to effector cells.
What are the two signals leading to stimulation and proliferation of T cells?
Signal 1: MHC peptide complex interacts with TCR on T cell. Signal 2: B7 receptor interacts with CD28 on T cell. Signal is enhanced via CD40 receptor that binds CD40 ligand on the T cell. The zone of contact between APC and T cell is called immunological synapse.
What are the lengths of synapse formation?
Synapse formation rapid in CD8 T cells. Synapse formation enduring (several hours) CD4 T cells.
What is the effect on APC?
Increased expression of co-stimulatory molecules e.g., B7. Also the APC is changed through the interaction and starts changing its gene expression and starts producing more and more different types of receptor on its surface or enzymes that help in the destruction of ingested pathogens.
What is the effect on T cell?
Induces T cells to express high affinity interleukin (IL)-2 and receptor and IL-2, IL-2 is a T cell growth and survival factor.
What is the outcome of CD8 T cell differentiation?
Cytotoxic T cells. 2 signals from APCs are required for this.
What do CD4 T cells differentiate into?
Multiple subtype. A third signal is required for this. Th1, Th2, Th17, Treg.
What are general properties of armed effector T cells?
Production and release of cytokines and related membrane associated proteins (such as receptors and immune modulatory functions), act by binding to specific receptors on the target cell (both CD8 and CD4).
What can the cell do after signal 1 and 2?
Now producing cytotoxic T cells that can and will kill infected cells.
What are the two main mechanisms of CD8 T cell mediated cytotoxicity?
- Perforin- polymerises to form transmembrane pores in target cell membranes to facilitate uptake of cytotoxins. Granzymes (one polymer) activate caspase 3 and apoptosis. Granulysin has anti-microbrial activity and can induce cell death.
2.IFN gamma- inhibits viral replication, facilitates antigen presentation through upregulation of MHC class I and II. Enhances the activity of CD4 Th1 cells.
What happens when the signals don’t both happen at the same time?
If there is only signal 1 then functional inactivation (no IL2 produced) of T cell and clonal deletion occurs. If only signal 2 occurs. There is no effect on the T cell.
What happens when both signal 1 and signal 2 are delivered by the same cell?
Naive T cell stimulated by virus-infected dendritic cell. T cell recognises same antigen on infected epithelial cell. Activated T cell kills infected epithelial cells. Naive T cell recognises self antigen on epithelial cell. Antigen-specific signal induces energy. T cell is unresponsive to self antigen on dendritic cell.
What happens in signal 3?
Determines differentiation of CD4 effector T cells. APCs principally dendritic cells release cytokines=signal 3. The specific form of signal 3 depends on the environmental conditions such as stage of infection, exposure to various pathogens.
At what different stages are the CD4 differentiated T cells used?
Absence of pathogens: Treg to produce relative abundance of TGF beta. Early infection: IL-6 + TGF-beta produced by Th17. Later infection: IFNgamma, IL-12 produced by Th1 and Th2 produces IL-4.
What do TH1 cells do?
Help to activate macrophage. Intracellular bacteria can be eliminated by activated macrophage. No need for co-stimulation. Armed CD4 TH1 cells synthesise membrane associated proteins and a range of soluble cytokines that co-ordinate the response to intracellular pathogens e.g., Mycobacterium tuberculnesis. 2 signals are required for this which are produced by T cells: IFN-gamma and CD40L.
How are the macrophages optimally activated?
IFNgamma and other surface molecules produced by CD40 ligand.
What do macrophages do once activated?
Activated macrophages make oxygen radicals and nitric oxide (made by inducible nitric oxide synthase). TH1 cells bind to macrophages for several hours=time required to synthesise effector molecules. CD8 T cells are also an important source of IFN gamma.
What is TH2s role in B cell antibody production?
Produced from release of IL4 by cytotoxic T cells. Inefficient macrophage activators as they produce IL-10 a cytokine that inactivates macrophages. Produce IL4 that activates naive antigen-specific B cells to produce IgM antibodies. Can subsequently stimulate the production of other isotypes e.g., IgA and IgE.
