Immunological Memory Flashcards
What are the general features of immunological memory?
Memory Cells are made during the primary immune response:
• Primary → first time the antigen is seen
• Secondary → second time the antigen is seen
• Tertiary → subsequent times the antigen is seen
- First time a pathogen is encountered, pathogen specific antibody and effector T cells are produced
- After the infection is cleared, these cells levels start to decline
- An early re-infection with the same pathogen is rapidly cleared, with few symptoms
- Reinfection years afterwards leads to an immediate and rapid increase in pathogen specific antibody and effector T cells as a result of memory, and disease symptoms are mild or inapparent.
• Memory is the most important aspect of the adaptive immune response, as it enables rapid response to previously encounted pathogens, preventing disease.
Memory cells don’t require constant exposure to antigen to survive:
• Memory reflects a small population of specialized memory cells that can persist in the absence of the antigen that originally induced them.
• This was established by observations of people on remote islands, where a virus such as measles can cause an epidemic, infecting everyone on the island at that time.
− On re-introduction of the virus after many years, the virus does not affect the original population, but does cause disease in those people born since the first epidemic.
Immunological memory is long-lived:
• Studies have attempted to determine the duration of immunological memory by evaluating responses in people who received vaccine (virus used to immunize against smallpox).
• Because smallpox was eradicated in 1978, it is presumed that their response represents true memory, and are not due to re-stimulation from time to time
• The study found strong specific CD4+ and CD8+ memory responses as long as 75 years after the original, and an estimated half-life of between 8-15 years
• Antibody titres remained stable, without measureable decline
Memory cells proliferate, but numbers remain constant:
• Most of the cells are in a resting state
• A small proportion may be proliferating at any one time
− Reason why is unclear
− Likely that cytokines produced either constitutively, or during antigen-specific immune responses to other pathogens are responsible
• The number of memory cells for an antigen is highly regulated, remaining practically constant → reflects a control mechanism between proliferation and apoptosis
How do the primary and secondary B cell responses differ?
Primary Response
• Primary response has antibody made by precursor B cells specific for different epitopes of the antibody, with different affinities
• Antibodies are overall relative low affinity, with few somatic hypermutations
• Rapid initial production of IgM accompanied by IgG lagging slightly behind (due to class switching).
Secondary Response
• Derives from a more limited population of high affinity B cells, which have undergone significant clonal expansion
• Their receptors and antibodies are of high affinity for the antigen with expensive somatic hypermutation
➢ This results in more intense and effective response
• First few days has small IgM production, large amounts of IgG and some IgA and IgE
− At the start of the secondary response, these are generated from memory B cells that have already undergone class switching in the primary response
• Higher levels of MHC-II
− Higher affinity and higher levels of MHC-II facilitate antigen uptake and presentation, which allows memory B cells to initiate their crucial interactions with T helper cells at lower doses of antigen than naïve B cells
− This means B cell differentiation and antibody production start early after antigen stimulation
− Secondary response therefore characterized by more vigorous and earlier generation of plasma cells, accounting for almost immediate production of IgG.
How does antibody affinity mature during each response?
- In secondary and subsequent immune responses, any antibody left over from the previous response is immediately available to bind to the newly introduced pathogen.
- If there is enough antibody, it is possible there will be no secondary response
- If pathogen overwhelms the antibody, a secondary response will be initiated:
Secondary response begins with proliferation of B and T cells at the interface between B and T cell zones, as in the primary response:
• Memory B cells continue to re-circulate through the same secondary lymphoid compartments as naïve B cells
• Memory B cells that have picked up antigen present peptide:MHC-II to the Tfh cells
• Tfh delivers signal 2 → leading to rapid proliferation of B cells
• As the higher affinity memory B cells compete most effectively for antigen, these B cells are the most efficiently stimulated in the secondary immune response
• Reactivated B cells migrate to the germinal centres
• Here, they undergo further somatic hypermutaiton before differentiating into plasma cells
• Affinity of antibodies produced rises progressively, because B cells with the highest affinity receptors will be selected to proliferation by interactions with Tfh cells each subsequent response.
So:
- Primary response → BCRs of a wife variety of affinity take up antigen and present it to Tfh cells, and be activated to produce antibody of varying and relatively low affinity. This will clear antigen, and only BCRs with high affinity will continue to capture antigen
- These B cells will be selected to undergo further expansion and clonal differentiation, and the antibodies they produce will dominate the secondary response
- The same process will happen again → these higher affinity antibodies will also compete for antibody, and only those of the highest affinity will be selected and form the tertiary response.
So in the secondary response you have lower B cell numbers but increasing quantify of antibody due to:
• High expression of surface Ig
• High affinity surface ig
• High ecpression of MHC-II
• High expression of co-stimulatory molecules
What are long-lived plasma cells?
• Memory cells may not produce all the antibodies in the secondary response
• Classic short-lived plasma cells make lots of soluble antibody during the immune response
• Long-lived plasma cells reside in the bone marrow and constitutively make antibody → important for maintaining antibody levels in the serum after infection
• On secondary exposure to antigen, pre-existing antibody can sometimes permit the formation of immune complexes which do not form immediately in the primary response:
− These can bind to Fc receptors on native B cells
− Acclerates the kinetics of their response
How do B cells commit to plasma cell or memory cell lineage?
If after Tfh stimulation of Naïve B cell: • BLIMP-1 is upregulated → short lived plasma cell • Bcl-6 is upregulated → maintenance and proliferation in the germinal centre − Undergo class switch and somatic hypoermutation
If after Tfh stimulation of activated proliferating B cell:
• BLIMP-1 is upregulated → long-lived plasma cell. BCMA required for their survival
• If BLIMP-1 isnt upregulated, you get differentiation to memory B cells
How do memory B cells reactivate?
• Re-exposure to antigen results in upregulation of BLIMP-1 and differentiation to plasma cells
What is the shift in understanding of the B cell memory response?
- Classically, memory B cells defined as expressing an isotype switched BCR that underwent affinity maturation in the GC
- Recent advances have found that both IgM and isotype switched memory B cells exist
- In addition, some memory B cells do not contain somatic hypermutations, and can be generated in a GC independent fashion.
- Study found IgM memory cells generated along with IgM memory cells in mice
- Not clear why the IgM did not switch isotypes → may be that those cells did not upregulate the required cofactors.
- These IgM show less mutations, showing less evidence of GC selection and affinity maturation.
GC-dependent and GC-independent memory B cell formation:
• Since not all B cells have somatic mutations or have undergone class switch, then germinal centres must not always be necessary
• Memory B cells are formed in mice that lack Bcl-6, so cant form germinal centres
• Seems the majority of IgM memory B cells are produced in an IgM independent manner, whereas class-switched memory B cells are GC dependent.
• The earliest memory B cells are detected only 3 days after priming, and this is well before the formation of GCs.
• These generate form the same activated precursor that gives rise to GC cells
• CD40 seems to have a role:
• Very strong CD40 seems to induce GC independent formation
• Weak CD40 seems to induce GC dependent formation
Functional Differences between IgM and class switched memory B cells
• IgM expands and proliferates similar to naïve B cells in reponse to antigen
• Class switched memory cells do not form GC cells and instead generate large amounts of plasma cells.
• Preferential localization of class switched memory B cells in the follicle, near Tfh cells, may contribute to the rapid memory
• Class switch have higher affinity (as already described)
• Role for IgM not so obvious seeing as it responds poorly in the presence of antigen:
➢ May be important during re-infection with mutated version of the pathogen
− Antibodies would bind to the mutant with low affinity
− Class switched memory cells would not be able to enter GCs and produce progeny with increased affinity
− Activated IgM memory cells would however, and they could enter GCs and undergo hypermutaiton that would result in a high affinity response to the new pathogen.
➢ The number of IgM memory cells remain stable whereas class switched memory cells decline over time.
− IgM may therefore function as an expanded population of B cells in the case that switched memory cells decline to below useful levels
− eg) human Hep B → vaccine specific antibodies drop to undetectable levels after a few years, but people still seem protected.
What are the characteristics of CD8+ memory T cells?
- Problem with identifying memory T cells is that the assays take several days, and the memory T cells can acquire effector activity during that time so they cant be distinguished
- This doesn’t apply to CTLs however, because CTLs can program a target cell for lysis in 5 mins, whereas a memory CD8+ T cell needs more time to be reactivated to become cytotoxic → so their effector functions will appear later.
• By staining clones of antigen specific CD8 T cells, it has been found that the number of antigen-specific CD8 increases during infection, then decreases 100 fold but is still higher than before priming.
• Express more Bcl2, a signal for sell survival
• The alpha subunit of the IL-7 receptor may be a good marker for activated T cells that will become memory cells:
− Naïve T cells express IL-7Ra, but this is lost upon activation and isn’t expressed on most effector cells
− In a mouse virus model, 5% CD8 T cells expressed IL-7Ra, and adoptive transfer of these cells could provide functional CD8+ T cell memory.
What are the characteristics of CD4+ memory T cells?
• Harder to study because responses are smaller than CD8
• Distinct from effector CD4+ T cells in that they require additional restimulation before acting on target cells:
− L-Selectin is lost on memory CD4+ T cells, but CD44 levels are increased on all memory T cells
− These changes contribute to directeing memory T cells from the blood into tissues rather than directly into lymphpid tissues
− CD25 isoform expression changes → enhanced CD45RO gives enhanced antigen recognition.
− These changes are charcteristics of effector T cells, yet some of the cells on which these chances have occurred have many characteristics of resting CD4+ T cells, suggesting they represent memory cells.
What are the two kinds of memory T cell?
Effector memory T cells:
• Can rapidly mature into an effector T cell and secrete large amounts of IFNy, IL-4 and IL-5 early after re-stimulation
• Lack the CCR7 receptor but express high levels of b1 and b2 integrins, and receptors for inflammatory chemokines
• This profile suggests effector memory cells are specialized for entering inflamed tissues
Central memory T cells:
• Expressed CCR7 and would therefore be expected to recirculate to the lymph node, as do naïve T cells
• More prone to TCR activation when they bind antigen
• Increased CD40L costimulatory molecule more quickly after antigen recognition
→ NB: although central memory T cells more likely to be reactivated due to lymph node homing, they do not get activated as quickly as effector memory T cells.
Why have 2 types?
• Effector → quick initial response, BUT short life span and low proliferation
• Central → take longer to gain effector function BUT provide a more long-lived response
How are memory T cells made?
- Most activated T cells become effector cells
- Many effectors are short lived and die by apoptosis
- Some activated and/or effector T cells become long-lived
- IL-7 and IL-15 are required for survival
- In order to be maintained, memory T cells need contact with self-peptide:self-MHC to continute to proliferate.
Development of CD8+ T cell memory involves CD4+
• Wild type and mice lacking CD4+ t cells have equivalent activity of CD8+ effector cells, but have fewer CD8+ memory cells.
• This requirement could be in the initial programming of CD8+ T cells during their primary activation to enable memory development. or it could be in providing help during the secondary memory response.
➢ Other experiments have inidicated they are needed during intial programming
➢ Memory CD8+ T cells developed in the absence of CD4+ T cells, then transferred into wildtype mice couldn’t amount a memory response even though they could now receive CD4+ T cell help.
➢ It is thought to involve signals through CD40 and IL-2 from the CD4+ T cell
− CD8 that don’t express CD40L cant generate memory cells
− CD8 with IL2-Ra deficiency cant generate memory cells
Do you get memory Th1/Th2 cells etc…?
- On stimulation by antigen, central memory T cells lose CCR7 expression, and differentiate into effector memory cells.
- Effector memory cells are heterogenous in the chemokine receptors they express → have been calssified according to receptors typical of Th1 (eg, CCR5) and Th2 (CCR4).
- Central memory cells are not yet committed to effector lineages
- Effector memory cells are not fully committed to the Th1 or Th1 lineage, although there is some correlation between Th1/2 output and the chemokine receptors expressed
