CD8+ T Cell Responses Flashcards
What are the characteristics of CD8+ T cells?
• CD8+ T cells recognize antigen bound to MHC-I
• Deliver death signals to target cell (so often called CTLs)
• Important in defense against intracellular pathogens → virally infected cells display viral proteins on MHC-I
• CTLs need activation first – MHC-I is on all cells of the body, if they didn’t need activation, it could be killing all the cells
− IL-2 causes proliferation and differentiation
− The cells acquire effector functions
− Effector CTLs will only kill target cells that given them signal 1 → after they’ve had 1-3 to differentiate and become a CTL, after that you just need signal 1 for effector function
• Naïve CD8+ T cells need more co-stimulation to drive them to become effector cells than naïve CD4+ T cells, perhaps because their effects are so destructive.
What is the direct activation method of CD8+ T cells?
- DCs have high intrinsic co-stimulatory activity and are specialized to present to CD8+
- Usually MHC-I presents intracellular antigens, but this would mean only virally infected DCs could present. But DCs can take up viral antigen and then present it on MHC-I → cross-presentation
- DC presenting antigen on MHC-1 → signal 1
- Requires high levels of co-stimulation (CD28/CD80) as the cells are so destructive
- This produces IL-2 which acts back on the T-cell to get proliferation of antigen specific CTLs
→ In some viral infections, DCs become sufficiently activated to directly induce CD8+ T cells to produce the IL-2 required for proliferation and differentiation, without help by CD4+ cells, but this is rare
What is the indirect activation method of CD8+ T cells
- In the majority of viral infections, CD8+ T cell activation needs additional help
- Because they need less co-stimulation to be activated, CD4+ T cells are usually activated first → so they are available to help with activation of CD8
- CD4+ T cells that recognise related antigens presented by the DC can amplify the activation of naïve CD8+ by further activating the DC
- CD80 on the DC induces the CD4+ cell to express IL-2 and CD40L
- CD40L binds to CD40 on the DC, inducing it to express more CD80, therefore providing more co-stimulation for the CD8+ T cell
- The IL-2 produced by the CD4+ T cell also promotes CD8 proliferation.
→ Other cytokines can then aid differentiation to CTLs, eg) IFNy by Th1
How do CTL granules cause killing of target cells?
- Serglycin acts as a scaffold protein for delivery of perforin and granzyme
- Perforin forms pores in the membrane
- The pores delivery granzyme or granulysin into the target cells
- Granzyme B cleaves and activates pro-caspase 3 → caspase 3, which is a cysteine protease that cuts after aspartic acid residues
- Caspase 3 activates a caspase proteolytic cascade, which eventually activates caspase-activated DNAase (CAD) by cleaving its inhibitory protein. This nuclease is believed to degrade DNA
- Granzyme B also targets BID → when BID is cleaved (either directly by Granzyme or indirectly via caspase 3), truncated BID disrupts the outer mitochondrial membrane, causing release of cytochrome C.
- Cytochrome C binds to APAF1, which activates caspase 9 → apoptosome.
→ Caspases can also inactivate PARP (a DNA repair protein), so there are resulting defects in DNA repair and activation of endonucleases causing DNA degradation.
- Cells undergoing apoptosis are rapidly ingested by phagocytic cells, which recognize a change in the membrane phosphatidylserine (normally found only in the inner leaflet, but not predominantly on the outer leaflet).
- Ingested cell is digested by the phagocyte without induction of co-stimulatory proteins → so apoptosis is immunologically quite – doesn’t contribute to an immune response.
How to CTLs control lymphocyte number?
Killing by CTLs does not always depend on granules:
• In contrast to killing infected tissue cells, this mechanism is used mainly to regulate lymphocyte numbers
- Activated lymphocytes express both Fas and Fas ligand, and thus activated CTLs can kill other lymphocytes through activation of caspases which induce apoptosis in the target lymphocyte
- Fas-FasL interactions are important in terminating lymphocyte proliferation after the pathogen initiating an immune response has been cleared.
- As well as CTLs, Th1 and Th2 cells have been shown to be able to kill cells by this pathway
- The important of Fas in lymphocyte homeostasis can be seen in patients with a mutant form of Fas → develop autoimmune lymphoproliferative syndrome
How do CTLs act by releasing cytokines?
- IFNy → inhibits viral replication directly, and induces increased expression of MHC-I and other proteins involved in peptide loading. This increases the change that an infected cells will be recognized as a target for cytotoxic attack
- IFNy → also activates macrophages, recruiting them to sites of infection as effector cells and APCs
- TNFa and LTa → synergise with IFNy in macrophage activation, and can help directly kill some infected cells by their interaction with TNFR-1, which induces apoptosis
How can CTLs be suppressive?
- When they see antigen in combination with IL-27 and input form CD4 cells, you get upregulation of BLIMP-1 which drives IL-10 production.
- This serves to limit inflammation and tissue damage
