Lecture 12- Effector responses against infectious agents Flashcards
How are CD4+ and CD8+ T cells activated?
Activated in similar ways.
Both require recognition of antigen to be activated.
Both require co-stimulation to be activated
What are the CD4+ and CD8+ T cell functions?
Cd4+ T cells become T-helper cells- produce cytokines, facilitate activation of other immune response
CD8+ T cells become cytotoxic T lymphocytes (CTLs)- directly kill cells infected with intracellular pathogens
How are cd8+ t cells get activated to become CTLs?
Get recognition with MHC class I.
Then signal 2.
CD8+ t cells don’t tend to have signal 3
once
When does cd8+ t cells need co-stimulation?
After initial activation, the CTL does not require co-stimulation to kill cell
What is the major way that CD8= CTLs kill cells?
By releasing granules
How does CTL kill an infected cell?
- CTL binds to target cell loosely
- CTL recognises antigen (presented by MHCI) and T-cell cytoskeleton reorganises to place granules at site of contact
- CTL released cytotoxic granules at the cell-cell contact = allows specific killing-> induces apoptosis
why is apoptosis better by CTL?
apoptosis produce less damage than necrosis- less inflammation induced
What’s in the CTL cytotoxic granules?
- Granzymes- serine proteases that induce apoptosis in target cell
- Granulysin-antimicrobial and can induce apoptosis
- Perforin- helps deliver granule contents to target cell
Why are all our nucleated cells potential targets for CD8+ t cells?
CD8+ cells recognise antigen in association with MHC Class I molecules, and all nucleated cells of body express MHC I
How do CTLs kill specifically?
CTL very directed killing of the cells that are expressing the pathogen’s antigens on the surface. Stops spread of virus
Apart from directly killing infected cells what do CTLs do?
Produce cytokines to regulate immune response (like CD4+ do)
e.g. interferon gamma which activates macrophages, increases MHCI expression in infected cells, inhibits viral replication
Which cytokines do CTLs produce?
- Interferon gamma which activates macrophages, increases MHCI expression in infected cells, inhibits viral replication
- TNFalpha and LTalpha- helps IFNgamma activate macrophages, can help directly kill some infected cells
what is the major way that CD4+ T helper cells do their jobs?
Production of cytokines-> regulate many different aspects of the immune response
How do CD4+ Th1 cells regulate immune response?
Generally mounted against intracellular pathogens-> viruses, some bacteria
In some infections, infection of the macrophage renders it inactive= needs activating to function
How do CD4+ Th1 cells activate macrophages?
-secretion of IFN-gamma
-CD40 ligand expressed on T cell-CD40 interaction
Activated macrophage upregulates MHCII- increased T cell activation (crosstalk)
(more slowly than CD8+)
Also produce IL3- induce macrophage differentiation. IL2 induces T cell proliferation
LT-alpha can kill infected cell.
In some circumstances what else can cd4+ th1 cells do?
Can stimulate some antibody production- IgG1 in humans and IgG2a in mice. Can opsonise pathogens in extracellular phase
what are some similarities between CD4 and CD8?
Both coordinate response against intracellular pathogens
Can activate macrophage via IFN-gamma and macrophage can make IFN-gamma itself
What do CD4+ Th2 cells fight?
Deal with extracellular pathogens e.g. worms
too big for cellular response or phagocytosis.
How do CD4+ Th2 cells regulate immune response?
- Help B cells produce antibody
2. Activate basophils, eosinophils and mast cells
What is an important antibody to deal with extracellular pathogens which CD4 Th2 activate B cells to produce?
IgE
How do CD4+ Th2 cells activate B cells to produce antibody?
interacts with B cell via CD40 then releases cytokines e.g. IL4,5,6 that activate B cell to proliferate, class swithc them to produce IgE
How do Cd4+ th2 cells activate basophils, eosinophils and mast cells?
directly via Th2 cytokines or indirectly via stimulation of B cells to make IgE which binds to cells and activates them
What do Cd4+ th17 cells fight?
generally against extracellular bacteria and fungi
How do CD4+Th17 cells regulate immune responses?
Produce IL17-> acts on several cell types to induce cytokine secretion
Neutrophil recruitment
stimulation of and macrophage and neutrophil production in bone marrow
Produce IL-22-> induces antimicrobial peptide production (at epithelial surfaces) act directly on extracellular pathogen to prevent it proliferating
how does an antibody kill the pathogen?
- Not directly toxic
- they facilitate destrcution of antigens by enhancing innate immune mechanisms:
1. Neutralisation
2. Agglutination
3. Opsonisation
4. Antibody-dependent cell-mediated cytotoxicity (ADCC)
5. Activation of complement
6. Specialised responses
1.antibody function- Neutralisation
Antibody binds to pathogen or toxin that pathogen’s producing to prevent attachment and entry into cell
2.antibody function- Agglutination
Clumping of particles to increase their ability to be taken up. Lattice work formed, more likely to be phagocytosed, can involve complement pathway (removal of immune complexes)
- antibody function- Opsonisation
antibodies coat the bacteria and then certain cells have receptors (e.g. macrophages have fc receptors) antibody binds to receptor and facilitates engulfing of bacteria. Helps macrophage recognise it and engulf.
4.antibody function- Antibody-dependent cell-mediated cytotoxicity (ADCC)
antibody binds to an infected cell or a large extracellular pathogen- too large to phagocytose
antibody forms bridge to immune cells via Fc receptors e.g. NK cells, macrophages etc.
mediates death of infected cell/pathogen
- antibody function- complement
trigger activation of the classical complement cascade
- antibody function-specialised response
e.g. IgE-mediated activation of mast cells- release of mast cell granules, lipid mediators and cytokines released
Initiates an inflammatory response- increased vasodilation, increased vascular permeability= accumulation of immune cells at site of infection
Summary of antibody actions?
- NEUTRALISING- pathogen/toxin to stop entry into cell
- AGGLUTINATING- to facilitate phagocytosis
- OPSINISING- pathogen/cell to facilitate phagocytosis
- ADCC- aid killing by immune cells
- COMPLEMENT- classical cascade activation
- SPECIALISED RESPONSES- e.g. IgE-mediated activation of basophils/eosinophils/mast cells
How have parasites adapted to avoid immune response?
parasitic worms have evolved to secret cytokine-like molecules to regulate host immunity
e.g. produce TGF-beta like molecules to induce Tregs, inhibits immune response against the parasite
