T-cells Activation and Polarisation Flashcards
(35 cards)
What are cytokines?
1) Small soluble glycoproteins (<30kDa) secreted by 1 cell that can alter behaviour/properties of cell itself or of another cell
2) Produced by lymphocytes, often called lymphokines and those secreted by monocytes/macrophages can be found as monokines
3) Many cytokines are referred to as ILs (interleukines)
What are some features of cytokines?
1) Work mostly over a short distance only
2) Relative ‘high’ local concentrations in micro environments (e.g., lymph nodes)
3) Effective in picomolar (10^-12M) concs.
4) Delicate functional balance between different cytokines within cytokine network
Why do cytokines act specifically?
Only cells expressing receptors for specific cytokines can be activated by them
Why do cytokines act locally?
1) Short-lived proteins and mRNA (few min/hr) - only cells in close proximity will be activated
2) High concs. of cytokines are needed for activation so only cells in close proximity will be activated
How can cytokines induce systemic effects?
E.g., induces secretion of acute-phase proteins by liver
What can TNF(alpha) do in low, moderate and high quantities?
1) Low - local inflammation, leukocyte activation
2) Moderate - systemic effects, fever –> haematopoiesis
3) High (plasma conc. >100nm) - septic shock, a systemic life-threatening inflammatory response
What is X-Linked SCID?
1) Severe combined immunodeficiency
2) Common gamma chain deficiency
3) Mutation in gamma chain –> loss of signal through IL-2, IL-4, IL-7, IL-9, IL-15
4) Immunocompromised and susceptible to infections
What are the properties of cytokines?
1) Pleiotropy
2) Redundancy
3) Synergy
4) Antagonism
How does activation of naive T cells by professional APC happen?
1) Signal 1 - antigen recognition and co-receptor ligation
2) Signal 2 - T-professional APC co-stimulatory interaction
3) Ag recognition induces B7 co-stimulatory molecules on APC
4) Signal 1 and 2 required for T cell clonal proliferation and differentiation to effector cells
What are resting T cells in the co-stimulation in T cells?
Express low affinity IL-2 receptor-beta and gamma chains and produce no IL-2
What is the role of Signal 1 in the co-stimulation in T cells?
1) NFAT binds to promoter of the alpha chain gene of the IL-2 receptor
2) The alpha chain converts IL-2R to a high affinity form (alphabetagamma IL2R)
What is the role of Signal 2 in the co-stimulation in T-cells?
1) Activates AP-1 and NFk-B to increase IL-2 gene transcription by 3 fold
2) Stabilises and increases half-life of IL-2 mRNA by 20-30 fold
3) IL-2 production increased by 100 fold overall
How does priming of effector T cells happen?
1) Activation of naive T cells by signal 1 and 2 allows T cells to proliferate and differentiate under control of autocrine IL-2 to an effector T cell
2) T cells are primed (armed)
In the absence of 2nd signal, what happens?
1) No activation of T cell
2) Anergy is induce - anergy is unresponsive state
3) Blocks ability of T cell to produce/respond to proliferative signals (even if later presented by competent APCs)
What are co-stimulatory molecules expressed by (APC)?
1) Dendritic cells, monocytes, macrophages, B cells
2) Not by cells that have no immunoregulatory functions (such as muscle, nerves, hepatocytes, epithelial cells)
3) Only some APCs, particularly DCs are able to prime naive T cells
How are CD8 T cells primed?
1) Immune system must be able to generate CTL responses (class I-restricted) to any infected/mutated nucleated cell
2) Dendritic cell ‘cross-presentation’ of ingested Ags on MHC class I
How does cross-presentation of Ags to CD8+ T cells?
1) Virus-infected cell –> infected cells and viral Ags picked by host APCs (Ag capture)
2) Cross-presentation –> co-stimulator (virus-specific CD8+ T cell) + viral Ag
3) T cell response
- Can explain how infection of non-professional PACs can lead to initiation of CD8 T cell response
How do dendritic cells have a critical role in immune response cancer?
1) Priming of CD8 T cells
2) Cross-presentation
3) Recruitment of CD4 help
4) CD4 + cDC1 + CD8 –> tumour
How do co-stimulatory molecules associate with inhibitory receptors?
1) Cross-linking of CD28 by B7 co-stimulates and induces CTLA-4
2) Cross-linking of CTLA-4 by B7 inhibits co-stimulation and inhibits T cell activation
3) CTLA-4 binds B7 with higher affinity than CD28 molecules to shut down T cell response
What is CD28?
1) Member of Ig superfamily
2) Needed for T cell secretion of IL-2
3) Constitutively expressed on T cell surface - upregulated after activation
What is CTLA-4 (or CD152)?
1) Is CD28 homologue
2) Cytotoxic T Lymphocyte Antigen-4
3) Its function is to downregulate T cell response
4) Protein and transcripts found inside cell - protein in Golgi vesicles, on cell surface after activation 24hrs with peak at 48-72hrs
What is the role of CTLA-4?
1) Physiologic terminator of T cell activation
2) Decline of normal immune response
3) Peripheral self tolerance
4) KO mice lacking CTLA-4 develop uncontrolled lymphocyte activation and infiltration of multiple organs, elevated Abs and autoAbs, mice die at 3-4 weeks
What are the roles of inflammatory Th1 cell cytokines?
1) IL-3: Growth of progenitor haemopoietic cells
2) GM-CSF: Myelopoiesis
3) IL-2: T cell growth
4) IFN-gamma: Macrophage activation, Induction of MHC class II, Inhibition of Th2 cells, CTL induction
5) TNF(alpha): Macrophage activation
6) TNF-beta: Cytotoxicity, Macrophage activation, Neutrophil activation
What are inflammatory T cell subsets for Th1?
1) IL-3
2) GM-CSF
3) IL-2, IFN-gamma, TNF(alpha), TNF-beta
