IMI 8: Immune Memory and Vaccination Flashcards
Describe the learning outcomes of the session
Is memory cellular or humoral?
- 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.
What is the primary role of B cells in immunity?
- 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.
What two cell types emerge from the germinal centre reaction?
- plasma cell: the effector B cell that make antibody
- memory B cell: the resting cell that is ready to respond next time
What is the quickest response the adaptive immunity can provide?
- 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.
Match the terminology to functions below to show what that antibody can do to prevent infections
What produces the antibodies in our body fluids?
Describe these cells
- 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.
Describe B-cell mediated immunity
- 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
Why would a memory B cell, which has already undergone affinity maturation, return to the germinal centre for more affinity maturation?
- 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.
What are the different subsets of memory T cells?
- 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.
Describe the relationship between memory T cell subsets
- 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.
Observe this diagram and describe the different memory T cell subsets: TSM cells (T stem cell memory cell)
- 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
Observe this diagram and describe the different memory T cell subsets: TCM cells (central memory T cell)
- 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
Observe this diagram and describe the different memory T cell subsets: TEM cells (effector memory T cell)
- 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
Observe this diagram and describe the different memory T cell subsets: TEFF cells (Effector T cells)
- 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
Observe this diagram and describe the different memory T cell subsets: TRM cells (resident memory T cells)
- 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
Do memory T cells have predefined roles?
- 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
How does immunological memory change the immune response?
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.
Look at this graph and describe the lag phase of the primary response
Where in the graph is this?
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
Look at this graph and describe the antibody response phase of the primary response
Where in the graph is this?
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
Look at this graph and describe the peak antibody level of the primary response
Where in the graph is this?
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
Look at this graph and describe when the primary response is over
Where in the graph is this?
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