Generation of Diversity in the T cell Repertoire Flashcards
What is an antigen?
β a molecule that can bind specifically to an antibody
What do adaptive immune reactions occur to?
β specific epitopes not the whole antigen
What is an epitope?
β A small portion of an antigen
What are epitopes a target for?
β TCR, antibodies and MHC
How many epitopes can one antigen have?
β Multiple
What do infection and vaccination induce?
β polyclonal T and B cell responses
What is the key difference between B cells and T cells?
β B cells recognise whole antigens and process them
β T cells donβt recognise native antigens
What happens when a B cell recognises a whole antigen?
β It receives additional activation signals
β the B cell proliferates and produces clones
β they all produce antibodies that are identical to the original B cell
How can T cells recognise antigens?
β The antigens must be processed for T cells to recognise them
What happens to the peptides that an antigen generates?
β they can be presented on the surface of an APC
What does a T cell need to do to be activated?
β interact with an antigen presenting cell to be active
What forms of an antigen will a T cell NOT have a response to?
β soluble native Ag
β cell surface native Ag
β Soluble peptides of Ag
β cell surface peptides of Ag
What form of antigen will a T cell have a response to?
β Cell surface peptides of Ag presented by cells that express MHC antigens
What types of APC will cause a T cell response and why?
β live APCs
β there are additional signals that only viable cells produce that can activate T cells
What are the 5 ways that exogenous antigens can be taken up?
β Phagocytosis β pinocytosis β Fc receptor mediated phagocytosis β complement receptor mediated phagocytosis β membrane Ig receptor mediated uptake
Which 4 immune cells recognise and process antigens?
β Monocytes
β Dendritic cells
β B cells
β macrophages
What are the main APCs?
β myeloid cells
β monocytes and macrophages
What is the most advanced type of APC?
β Dendritic cells
What is the difference between macrophages and monocytes?
β monocytes are blood circulating cells
β macrophages are in tissues and are terminally differentiated monocytes
What two cell types can monocytes become?
β dendritic cells or macrophages
Where are dendritic cells found?
β mucosal tissues
What do dendritic cells induce?
β strong T cell responses and inflammation
What are macrophages better at doing than dendritic cells?
β better equipped to kill pathogens
β NO production
What are dendritic cells better at doing than macrophages?
β migrating to lymph nodes via CCR7 and presenting antigens to T cells
Where are B cells highly abundant?
β In mucosal tissues
How do B cells internalise antigens?
β receptor mediated internalisation
What is the primary function of B cells?
β to make antibodies but they are still good at antigen presentation
What bacterium are dendritic cells important against?
β Mycobacterium tuberculosis
What cell is the main inducer of the T cell immune response to neisseria meningitidis?
β B cells
What are the 4 steps for endogenous antigen processing?
β Uptake
β degradation
β antigen-MHC complex formation
β Presentation
When is endogenous antigen uptake done?
β when the antigens/pathogens are already in the cell
What is endogenous antigen degradation?
β Pathogenic antigens synthesised in the cytoplasm undergo limited proteolytic degradation in the cytoplasm
What is the antigen-MHC complex formation?
β loading of the peptide antigens onto MHC class I molecules
What is presentation of endogenous antigens?
β transport and expression of antigen MHC complexes on the surface of cells for recognition by T cells
What are macrophages specialised for?
β motility, phagocytosis and the introduction of particles to the lysosomal system
Why is a non-lyosomal mechanism to process antigens necessary?
β most cell types do not have lysosomal systems but viruses can infect most cell types
How does cytosolic presentation occur?
β The viral protein is in the cytosol
β It enters the proteasome
β It is cleaved into multiple peptides
β loaded onto MHC class I and presented on the cell surface
How are antigens from inactive viruses processed?
β via the exogenous pathway
What kind of a response do inactive viruses raise?
β a weak cytotoxic response
What kind of drugs is the processing of antigens from inactive viruses sensitive to?
β lysosomotropic drugs
What is required for non-lysosomal antigen processing?
β protein synthesis
How are antigens from infectious viruses processed?
β via the endogenous pathway
Describe the endogenous pathway/Class I pathway?
β The antigen is processed
β it is cleaved into multiple peptides
β presented on the MHC class I on the surfaces
β MHC I activates a CD8 cell
Describe the endosomal pathway?
β Antigens are endocytosed by macrophages
β They are sequestered to lysosomes or endosomes
β Processed in the lysosomes and loaded onto MHC II molecules within the lysosomes
β MHC II activates a CD4 T cell
Where are Exogenous pathogens directed?
β MHC II
Where are Endogenous pathogens directed?
β MHC I
How are exogenous pathogens eliminated?
β Antibodies and phagocyte activation by T helper cells that use antigens generated by exogenous processing
How are endogenous pathogens eliminated?
β Killing of infected cells by CTL that use antigens generated by endogenous processing
Where is MHC I expressed?
β all nucleated cells
Where is MHC II expressed?
β on APCs and activated T cells
What does MHC I bind to?
β short peptides
β 8-10 amino acids
What does MHC II bind to?
β long peptides
β 15-24 amino acids
What does MHC I present to?
β CD8+ T cells
What does MHC II present to?
β CD4+ T cells
Where does MHC I get its antigens from?
β from the cytosol
Where does MHC II get its antigens from?
β Phagosomes and endosomes
How many MHC class I isotypes are there?
β 6
How many MHC class II isotypes are there?
β 5
What are the similarities between TCR and BCR?
β Belongs to Ig superfamily
β Like Fab fragment of antibody
β large diversity
β single specificity
What are the differences between TCR and BCR?
β Lower affinity
β cannot be released
β no Fc fragment so no cellular functions
β single binding site not two
βBCR has 5 classes
β TCR has 2 classes alpha beta and delta gamma
What are the two mechanisms that generate BCR diversity?
β Before antigen stimulation : somatic recombination
β after antigen stimulation : somatic hypermutation
What is the mechanism that generates TCR diversity?
β before antigen stimulation : somatic receombination
β after antigen stimulation : none
When does receptor gene rearrangement take place?
β during T cell development in the thymus
What is the three signal mode of activation for T cells?
1) peptide-MHC (pMHC)
2) Co-stimulation
3) Cytokines
What is the third signal important for when activating T cells?
β amplification of the response and determining T cell phenotype
How is the peptide-MHC signal delivered to the T cell ?
β The main signal (1) is delivered from the APC by a peptide-MHC complex to the TCR
How is the co-stimulatory signal delivered to the T cell?
βThe co-stimulatory signal (2) is delivered from the APC by germline-encoded accessory receptors such as the B7 family (CD80 and CD86)
What type of T cell does IL-12 promote?
βTH1 cells
What type of T cell does IL-4 promote?
βTH2 cells
What type of T cell does IL-23 promote?
βTH17 cells
What is the immunological synapse?
β signals 1 and 2 are central
β surrounding integrins and accessory molecules help to stabilise the interaction
What is the central interaction in the immunological synapse?
β T cell and peptide-MHC complex
What is the central interaction like in the immunological synapse?
β short lived and has a low affinity
What are the co-stimulatory molecules that promote T cell binding and what do they interact with?
β CD80/CD86 or B71 and B72 interacting with the T cell partners CD28 and CTLA4
What is the function of the co-stimulatory molecules?
β They strengthen the activation of the two cells and provide additional signals for the activation of the T cells
What is the function of integrins during T cell binding?
β keep the cells in contact
What are the pathways used in peptide-MHC binding to TCR and what is the effect?
β Lck
β Zap70
β PLC- gamma
β effect : calcium flux & NFAT activation
What are the pathways used in co-stimulation and what is their effect?
β PI3K
β Akt
β MAPK
β effect : NF- kappa B activation
How are T cell co-receptors expressed?
β co-expressed with the TCR
How many co-receptors do the T cells have?
β one
What do CD4 cells do?
β help other cell types by secreting cytokines
What do CD8 cells do?
β kill infected cells directly
What do TH1 cells do?
β produce cytokines which will activate macrophages and the macrophages will kill intracellular pathogens more efficiently
What do TH2 cells do?
β Produces other cytokines which activate B cells and the B cells will then produce antibodies and neutralise circulating viruses and prevent colonisation of bacteria
What do negative regulators of antigen presentation do?
β provide an immune checkpoint to limit T cell activation
What are the two important molecules in T cell regulation?
β CTLA4 (cytotoxic T lymphocyte associated protein)
β PD-L1 (programmed death ligand 1)
Describe how PD-L1 and CTLA-4 work to inhibit T cell function?
1)The T cell receptor interacts with APCs which leads to T cell activation
2)PD-1 is expressed on T cells
If it is activated by PD-L1 (ligand) it leads to a blockade of T cell receptor activation
3)This is through multiple signalling pathways
4)CTLA-4 acts on the co-stimulatory molecules (both signal 1 and 2 are important for T cell activation)
5)Both signals can be blocked with CDLA-4
What is positive selection in the thymus?
β T cells that canβt bind self antigen-MHC are deleted
β these cells are useless because they wonβt protect against pathogens
What is negative selection in the thymus?
β T cells that bind self antigen-MHC too strongly are also deleted
β these cells are dangerous because they are too self reactive
What is the stochastic model?
β A proportion of T cells that are strongly reactive to self-antigen will express the transcription factor FOXP3 which is the βmaster controller of regulatory T cells
What can Treg cells do?
β they can compete with any autoreactive T cells and secrete anti-inflammatory cytokines
What are Treg cells also called?
β CD25
What do Treg cells secrete?
β interleukin 10 and TGF beta
What are obligate parasites?
β organisms that depend on the human host for survival
How does mycobacterium tuberculosis evade the immune system?
β Upregulated PD-L1 on APCs to shut down T cell activation β Blocks MHC class II expression
How does neisseria meningitidis evade the immune system?
β Blocks DC activation which decreases CD40, CD86 and MHC class I and II expression β Antigens are homologous to self-antigens so anergic T cells
How does Neisseria gonorrhoea evade the immune system?
β It expresses Opa protein which binds to.T cells and induces tyrosine phosphatases that βswitch offβ key molecules involved in TCR signalling
How does HIV evade the immune system?
β Upregulates PD-1 on T cells which antagonises TCR signalling
β Binds to DC-SIGN to suppress DC activation via Rho-GTPases
How does HSV evade the immune system?
β Produces protein which binds to and inhibits TAP
β prevents viral peptide transfer to the ER
How does adenovirus evade the immune system?
β Produces protein which binds MHC class I molecule β prevents MHC class I from leaving the ER
