IMI 8: Immune Memory and Vaccination Flashcards
1
Q
Describe the learning outcomes of the session
A
2
Q
Is memory cellular or humoral?
A
- In 1890 the German scientist Emil von Behring and Japanese the physician Shibasaburo Kitasato, working together in Berlin, demonstrated that the transfer of serum from a mouse immunised against tetanus to a non-immunised mouse could completely protect the latter from a normally fatal challenge with virulent tetanus bacteria.
- While this observation supported Paul Ehrich’s model of humoral factors being the critical mediators of immunity, it turns out that this kind of humoral immunity is relatively short-lived.
- Subsequent adoptive transfer experiments – where various sets of cells from immunised mice are transferred to immunologically naive mice – showed that certain subsets of B and T lymphocytes are the key elements in the potentially life-long immunity that we develop after infection or vaccination.
3
Q
What is the primary role of B cells in immunity?
A
- The primary role of B cells in immunity is the development and production of high affinity specific antibodies.
- To be pre-armed against re-infection, the body needs both an abundance of antibodies in the body fluids (be it blood, lymphatics or mucosal surfaces), and cells that can accelerate the production of more antibody when a re-infection occurs.
- It may be a surprise to you that for any given antibody, these two jobs are done by different B cell subsets.
4
Q
What two cell types emerge from the germinal centre reaction?
A
- plasma cell: the effector B cell that make antibody
- memory B cell: the resting cell that is ready to respond next time
5
Q
What is the quickest response the adaptive immunity can provide?
A
- antibody-mediated immunity
- having sufficient levels of specific antibody where a pathogen invades.
- This way, the antibody is ready and able to bind to the antigen as soon as it arrives!
- If the antibody can intercept the pathogen before it gets a chance to properly invade or proliferate, then the infection will be stopped before it even begins.
6
Q
Match the terminology to functions below to show what that antibody can do to prevent infections
A
7
Q
What produces the antibodies in our body fluids?
Describe these cells
A
- The antibodies in our body fluids are produced mainly by long-lived plasma cells that take up residence in our bone marrow and mucosal tissues (e.g. gut, lung).
- Despite being a terminally differentiated cell type, these plasma cells appear to be able to survive extremely long periods of time.
- This may in part be because they express very low levels of the B cell receptor (BCR), which means they are not easily activated when encountering antigen.
- As a result, these long-lived cells do not boost body-wide antibody production, but rather are responsible for maintaining a baseline of antibody production in the long term.
8
Q
Describe B-cell mediated immunity
A
- Most of the B cell output of the germinal centre during an initial immune response will take the form of memory B cells.
- Early in the response, many of these memory cells will retain IgM production, having not class-switched.
- Later in the response, the majority of memory cells leaving the germinal centre will have class switched, to IgG, IgA or IgE, depending on the nature of the signals provoked by the pathogen.
- These will also have Ig with a higher affinity for the target.
- In comparison with naïve B cells, memory B cells are also resting cells, with low metabolic rates.
- However, they are able to respond more rapidly to activation signals than naïve cells.
- This is in part because they have more of the activating receptors such as CD40, CD80 and CD86 on their surface.
- They are also more sensitive to stimulation by PAMPs.
- In general, however, memory B cells have many of the same restrictions and actions as naïve cells.
- They require T cell help, BCR binding and an innate signal (through cytokine signals and/or sensing of PAMPs) to trigger their activation and proliferation.
- -Some of these cells then differentiate into plasma cells to produce antibodies, while others – particularly the lower affinity IgM subset – will migrate to the germinal centre to undergo further affinity maturation
9
Q
Why would a memory B cell, which has already undergone affinity maturation, return to the germinal centre for more affinity maturation?
A
- We have seen in IMI5 and IMI6 that some pathogens are constantly changing the epitopes that can be recognised by antibodies.
- To adapt to these changes – particularly to antigenic drift – keeping diverse Igs with low affinity as memory B cells, makes it more likely that some of those will still be able to recognise a modestly mutated antigen.
- This will then act as a basis for producing new high affinity Igs against this modified pathogen, protecting against a wider variety of strains.
10
Q
What are the different subsets of memory T cells?
A
- T cells that have encountered antigen previously are less easily defined, since their TCR remains unchanged.
- Nevertheless, the body wants more ready access to those T cells whose TCR has already recognised antigen, thereby proving itself to be potentially useful in future.
- For T cells there are, therefore, a number of different subsets of memory T cells that have been defined based on their locations in the body and their cytokine, receptor and metabolic profiles.
- These properties will give them different roles in subsequent immune responses.
- All of these memory T cells are primed to respond more readily than naïve T cells, in response to their TCR being presented with antigen.
- All of the memory T cells are relatively long-lived.
11
Q
Describe the relationship between memory T cell subsets
A
- How these different subsets relate to each other is still not fully understood but there appear to be subsets that are more pluripotent (i.e. more able to give rise to many different cell types) or closer to terminal differentiation than others.
12
Q
Observe this diagram and describe the different memory T cell subsets: TSM cells (T stem cell memory cell)
A
- TSCM (T stem cell memory cells):
- TSCM are memory cells that are capable of differentiation into various other types of memory T cell
- this subset was discovered in mice, but its existence in humans has not yet been proved
- it may be that this type of cell is the origin of the other types, which may be constantly replenished in the blood
13
Q
Observe this diagram and describe the different memory T cell subsets: TCM cells (central memory T cell)
A
- TCM (central memory T cell):
- they are found in both secondary lymphoid tissue and in the circulation
- they are the most long-lived T cell type and secrete relatively few cytokines at rest
- they can give rise to both TEM and TRM cells
- it is this subset that is most likely activated for helper functions in the lymphoid tissues
- e.g. helping B cells refine their antibodies
- this location allows them to be rapidly activated when peripheral dendritic cells arrive in lymph nodes with antigen that their TCR can detect
14
Q
Observe this diagram and describe the different memory T cell subsets: TEM cells (effector memory T cell)
A
- these cells are memory cells found in tissues or in the circulation
- they lack receptors that would drive them to relocate to the secondary lymphoid organs
- e.g. lymph nodes
- they will respond to APCs (CD4+ memory) or infected/cancerous cells (CD8+) memory in the blood or tissues
15
Q
Observe this diagram and describe the different memory T cell subsets: TEFF cells (Effector T cells)
A
- these are the T cells we have spoken about previously; the T cells that are activated and get out and do the job of detected presented antigen
- either to provide help (CD4+) or kill offending cells (CD8+)
- memory cells can change into effector cells in response to stimulation
- it is not clear whether they can return to a memory state once they have changed
- it is thought that a CD4 memory T cell can become any one of the various subsets of cells (TH1, TH2, TH17, Treg etc.) that are effector T cells
- this will depend on the nature of the response and the cytokine environment
16
Q
Observe this diagram and describe the different memory T cell subsets: TRM cells (resident memory T cells)
A
- TRM cells that are present in tissues, in a position to respond locally to an invasion of a pathogen
- they tend to be more mobile, actively patrolling tissues
- and more metabolically active
- and as a result perhaps more short lived) than other memory cell subsets
- these are likely to be the first to come across antigen at a site of infecton
17
Q
Do memory T cells have predefined roles?
A
- Because the CD4 or CD8 status of the T cells is largely defined by whether their TCR recognises peptides on class I or class II MHC molecules, memory cells also retain this property: that is to say that a CD8+ memory T cell will always reactivate into a cytotoxic T cell.
- It cannot, for example, become a CD4+ T cell.
- However, the CD4+ T cell subset, which can have a variety of different helper functions, is not generally a predefined property of the memory cell.
- So, for instance, a CD4+ memory T cell has the potential to become a TH1 cell or a Treg, and this is solely dependent on the signals (cytokines, PAMPs, etc) that it encounters when its TCR is activated by an antigen
18
Q
How does immunological memory change the immune response?
A
Once you have established memory to a pathogen, subsequent responses will be improved in several different ways.
- Antibodies from long-lived plasma cells secreted into your circulation and lymph, diffuse into the spaces between cells in the tissues.
- And in the case of an IgA response the antibodies are also secreted onto the mucosal surfaces of the body.
- Once antibodies are secreted they will all be able to directly act against the pathogen.
- This will allow opsonisation and complement fixation of infectious agents, and perhaps neutralisation, particularly of non-enveloped viruses which can be eliminated by TRIM21 even with a small amount of antibody binding
- The basal levels of antibodies in our extracellular spaces will stave off small scale invasions, which means that a more concerted attack will need a more active and dedicated response.
- Here the cellular memory will be important.
- Memory B cells need to be activated to differentiate into plasma cells to produce more antibodies, or cytotoxic T cells (CTLs) need to be activated to identify infected cells.
- Both of these processes usually also require T helper (TH) cells.
- While the response could start in the tissues, it is most likely that a strong response would come only once the antigen has been transported to the large collections of immune cells in the secondary lymphoid tissues.
- Kind of like taking your evidence to the police HQ so that the officers who can ID the criminal are sent out to track him down!
- Because the activation of the cellular adaptive response needs to bring T helper (TH) and B cells together, and because it may also need the specific cells to proliferate into a decent fighting force and to differentiate into effector cells (particularly plasma cells), this response takes longer to mobilise than the humoral immune response.
- Nevertheless, the response will often reach a potent level within a day or two, in contrast to the 4-7 days more typical of a primary immune response.
19
Q
Look at this graph and describe the lag phase of the primary response
Where in the graph is this?
A
The first point
- Lag phase:
- before the immune system can produce large amounts of specific antibodies, a lot has to happen
- both T cells and B cells with receptors specific for the antigen must proliferate and then somatic hypermutation and clonal selection of the B cells for high affinity Ig takes place in the germinal centre
- this can take 4-7 days or more to generate decent quantities of high-affinity antibodies
- as a result, there is a lag in the antibody response
- if the pathogen is not completely controlled by the innate immunity, this period is characterised by increase in the amount of pathogen
20
Q
Look at this graph and describe the antibody response phase of the primary response
Where in the graph is this?
A
second point on graph
- antibody response:
- at last the B cells have been selected to make high affinity antibodies and they can differentiate into plasma cells that provide antibody at the site of infection and into the wider boy fluids
- this will rise while the B cells are stimulated by antigen, but stop rising when the infection is cleared
21
Q
Look at this graph and describe the peak antibody level of the primary response
Where in the graph is this?
A
third point on the graph
- peak antibody level:
- new antibody is no longer being produced
- because antibody has a half-life of around 2-4 weeks, there will be a period after the infection has been resolved when the antibody levels remain high
22
Q
Look at this graph and describe when the primary response is over
Where in the graph is this?
A
fourth point on the graph
- primary response is over:
- at the end of the primary response, the level of antibodies against antigen A falls to a steady level
- this level is higher than it was before the first challenge
- and the antibodies will probably have higher affinity and avidity
- these new high affinity antibodies are continually produced by long-lived plasma cells
- over a very long time (varies case by case) the level of specific antibody will slowly fall if the person does not encounter the antigen again
- there has been no change in levels of antibodies against antigen B because B cells have not yet encountered it
23
Q
Look at this graph and describe the rapid secondary response
Where in the graph is this?
A
first point in secondary response
- the production of antibodies against antigen A is triggered by the activation of memory B ells and their differntiation into plasma cells that secrete antibodies
- this process is supported by the activation of T helper cells specific for peptides from antigen A
- note the much shorter lag (1-2 days) that it takes before antibody levels increase
24
Q
Look at this graph and describe the long term antibody levels in the secondary response
Where in the graph is this?
A
- the long term resting antibody levels may be higher after the secondary antigen exposure than they were after the primary response finished
- this probably depends on how effective the primary response was
- repeated stimulation by a pathogen is likely to maintain higher antibody levels than a one-off challenge
25
Q
Look at this graph and describe the response to antigen B in the secondary response
Where in the graph is this?
A
end of secondary response
- this is the first time that the immune system has encountered antigen B, so this will still be a primary response, despite there being a secondary response to antigen A
- there will again be a lag while B cells undergo activation, migration, clonal selection, class switching and differentiation to plasma cells before specific antibody levels rise
- it will only be quicker if antigen B shares T cell epitopes with antigen A
- in that case, the naive B cell response may be helped to develop a little bit more quickly by having a larger number of specific memory T helper cells ready to go
- however, since antibody maturation is the slowest part of the process, it is unlikely to make a big difference
26
Q
During a memory response, which of the following cells produce factors that can directly damage an invading pathogen?
A
- cytotoxic T cell
- plasma cell
The cells that actually do all the dirty work are mainly the same in a memory response as a primary response.
- The effector cells (CD8+ T cells or plasma cells) are producing the adaptive response, although resident memory and effector memory CD8+ T cells may also be able to combat pathogens directly without first differentiating into effector cells.
- CD4+ T cells play a support role for these effectors (and for innate cells), so do not directly combat the pathogen.
27
Q
Which facets of the memory response are relevant to combating a virus infection?
A
- antibodies (from long lived plasma cells)
- Antibodies (from activated memory B cells)
- Activation of CD8+ T cells
- Activation of CD4+ T cells
28
Q
Which facets of the memory response can help combat an extracellular bacterial infection?
A
- antibodies from long lived plasma cells
- antibodies from activated memory B cells
- activation of CD4+ T cells
29
Q
Describe different types of vaccines and give examples of each
A
- live attenuated (LAV)
- versions of the pathogen with reduced virulence
- they can infect and spread in the person, but don’t cause disease
- may cause problems in the immunosuppressed
- inactivated (killed antigens):
- whole pathogens that have been chemically wrecked so they cannot infect cells or replicate
- only presented to the extracellular immune system
- subunit (purified antigens):
- consist only of a part derived from a pathogen or antigen
- e.g. bacterial surface proteins or viral glycoproteins, pillin proteins or toxins
- very safe, but may require booster vaccinations
- toxin (inactivated toxins):
- use a chemically disabled form of the purified toxin to promote immunity to a bacterial toxin
- these vaccines protect against the harmful consequences of the infection, but do not establish immunity to the bacterium, just the symptoms it causes
30
Q
Using what you know about immune responses, and how antigens are presented to the immune system, see if you can match the type(s) of adaptive immune response that will be induced each type of vaccine.
A
- So, how can you work out what responses are induced by what vaccines?
- You need to consider where and how the antigens can be sensed, presented and detected by the adaptive immune system.
- A live virus will synthesise its proteins (antigens) inside a cell.
- Some of these proteins will be chopped up to generate an MHC Class I antigens, which can induce a cytotoxic T cell response.
- Antibody will be made against any antigens exposed to the extracellular space: initially this could be membrane glycoproteins on the vaccine, and then on any viruses that emerge from (or are left on the surface of) the infected cells.
- The intracellular viral proteins will probably only induce an MHC class I-based cytotoxic T cell response, but could also induce an antibody response if they leak out when the infected cells die.
- Extracellular pathogens or antigens will generate an antibody response, but not a CTL response.
- Thus, the inactivated virus, single protein and toxoid vaccines will develop antibodies but not cytotoxic T cell responses.
- In contrast, nucleic acid vaccines (DNA or RNA constructs that make antigens when they get into cells) will make a CTL response, and also antibody if it is exposed to the extra-cellular space.
- The extent to which a response induces T helper cell responses will depend on the nature of the antigen:
- A T-cell independent antigen (something repetitive, and/or with a strong PAMP) may elicit a B cell/antibody response without generating a CD4+ T cell response.
- The diversity of antigens in a whole virus vaccine means inducing a CD4+ T cell response is more likely, whereas a protein antigen may be less effective at establishing CD4+ T cell memory.
All of these memories will be stored as memory B or T cells, to be able to respond much quicker to assault by the actual pathogen.
34
Q
Why is the polio eradication campaign unfinished?
A
- After the success of the smallpox eradication campaign, in 1988 the World Health Organisation (WHO) targeted polio for elimination by the year 2000.
- The map below highlights how polio eradication remains elusive 20 years beyond that initial goal.
- Because oral polio vaccine is effective – establishing lifelong protection from infection – as well as cheap and easy to administer, it has been the mainstay of the polio eradication campaign.
- As a result, wild-type polio now circulates only in conflict-associated regions of Nigeria, Pakistan and Afghanistan (red in the image above).
- However, because the vaccine is a live virus, it has been shed into the environment, and where sanitation is poor, it is able to continue to circulate.
- Worse, by circulating in people, the virus has reversed some of its attenuating mutations, meaning that the vaccine-derived polio has evolved to again be able to cause disease.
- Frustratingly, there are now more cases of polio disease caused by vaccine-derived polio than the original virus!
- Once polio is eradicated, we will need to stop vaccinating, but if the vaccine strain is still circulating, then it has the potential to spread into unvaccinated youngsters.
- The obvious solution is to switch to the IPV, but this is both much more expensive to manufacture and deliver, and may not even be able to prevent the circulation of polio, because it fails to induce gut immunity.
- This remains a thorny problem for the eradication campaign to solve.
41
Q
Describe conjugate vaccines
A
- Some potential antigens are very poorly immunogenic, but if an immune response against them was raised, it would be protective.
- This is particularly true of non-protein antigens, such as bacterial surface polysaccharides that are joined to lipids (lipopolysaccharide – LPS).
- Conjugate vaccines join a non-immunogenic antigen to a protein, so that it becomes more easily identified by the immune system.
- This approach has revolutionised the production of anti-bacterial vaccines in recent years, but is not a normal antiviral vaccine strategy.
42
Q
Describe nanoparticle vaccines
A
- A recent adaptation of subunit vaccines is to engineer them into a more virus-like form.
- This can use either an artificial bead, lipid droplet or can rely on the ability of (some) virus capsids to assemble spontaneously from their component parts.
- Different types have different properties, but having a small and repeating profile better resembles a pathogen surface, and may enhance antibody production through T-independent mechanisms.
- The human papilloma virus vaccine is made from its capsid protein, which self-assembles into a virus-like particle.
43
Q
Describe virus-vectored vaccines
A
- Another way of persuading cells to make antigen to provoke an immune response is to carry an expression cassette in the shell of a harmless virus.
- The virus is generally a strain that has been attenuated so it does not replicate efficiently and does not detrimentally affect the immune response, but has all the material to deliver an antigen-producing gene to the cells.
- Because viral vector vaccines result in endogenous antigen production, both humoral and cellular immune responses are stimulated.
- The main platforms being used for this approach are the poxviruses that smallpox elimination has shown is hugely immunogenic, and the adenoviruses expressing the SARS-CoV-2 spike protein that have emerged during the COVID-19 vaccine response.
44
Q
What is the reproduction number (R0)?
Describe the different R0s of different viruses
A
- the R0 is the average number of times an infected individual transmits their pathogen to a new person
- Viruses that have recently spread from animals (such as pandemic influenza virus, Ebola virus or SARS-CoV-2) often do not spread easily between humans, so they tend have a small R0.
- As these zoonotic viruses evolve and adapt to their new host, the R0 can increase.
- The R0 numbers in this figure assume that no protective action is taken.
- However, environmental factors can alter this number: practising safe sex, or antiretroviral treatment can reduce the R0 of HIV to almost zero.
- Hygiene control measures, such as changes in how bodies were handled during the West African Ebola outbreak reduced the R0 of Ebola virus, helping to control the 2014-2015 Ebola pandemic.
- Having a vaccinated population also reduces the effective R0 of a virus, by limiting the number of vulnerable contacts to whom the virus can spread.
