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IL-21 androutes
T follicular
helper
cells
Multiple
to B-cell
memory
Rosanne Spolski and Warren J. Leonard
Kim L. Good-Jacobson1,2 and David M. Tarlinton1,2
Laboratory
1
of Molecular Immunology, National Heart, Lung, and Blood Institute, Building 10, Room 7B05, Bethesda,
Immunology
Division,
20892-1674,
USA Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia
MD
2
Received 23 January 2012, accepted 4 March 2012
Abstract
Abstract
Upon encounter with antigen, CD41 T cells differentiate into effector Th subsets with distinctive
functions that are related to their unique cytokine profiles and anatomical locations. One of the most
B-cell memory describes the populations of cells that provide long-term humoral immunity: long-lived
important Th functions is to provide signals to developing B cells that induce specific and appropriate
antibody-secreting
plasma cells that reside mainly in the bone marrow and memory B cells. Interestingly,
antibody responses. The major CD41 T cell subset that helps B cells is the T follicular helper (TFH) cell,
the memory B-cell population is heterogenous, although the importance of this heterogeneity has
been
whose expression of the chemokine receptor CXCR5 [chemokine (C–X–C motif) receptor 5] serves to
unclear. Recent studies have investigated the formation and function of memory in different settings.
localize this cell to developing germinal centers (GCs) where it provides instructive signals leading to
In particular, T-independent memory-like cells and T-dependent (TD) IgM memory B cells qualitatively
Ig class switching and somatic mutation. TFH cells produce high levels of IL-21, a cytokine that is
differ from canonical TD class-switched memory
B cells; however, these studies suggest that IgM
critical for GC formation and also for the generation of TFH cells. Although TFH cells have been found
memory cells preserve the memory population over long periods
of time. These subsets are evocative of
to produce cytokines characteristic of other T subsets, they represent a distinct lineage whose
the evolution of the humoral immune response,hwith memory-like cells appearing before acquisition of
development is driven by the transcription factor B-cell CLL lymphoma-6 (BCL6). Consistent with
germinal centers, suggesting that there are multiple pathways to producing B-cell memory.
their critical role in the generation of antibody responses, dysregulated TFH function has been
associated with the development of systemic autoimmunity. Here, we review the role of IL-21 in the
Keywords: antibody, evolution, IgM memory, plasma cells, T-independent
regulation of normal TFH development and function as well as in progression of autoimmune
responses.
Introduction
Keywords: autoimmunity, BCL6, germinal center, Th subsets
The immune system has one fundamental function—to recognize foreign invaders and reject them from the body, while
ensuring that such defense mechanisms do not destroy the
host. This function remains the center around which the
immune
system, at the cellular, biochemical, genetic and
Introduction
epigenetic levels,
has evolved. The immune system has also,
Specific CD4+ T cell effector responses can be delegated
at various points in evolution, acquired the ability for heightto distinct subsets characterized as Th1, Th2, Th17 or reguened responses to pathogens if the host
had been infected
latory T cell (Treg) cells, with the development of each of
prior—this is termed immune memory. As such, patients with
these subsets being driven, respectively, by the master
immunodeficiencies that affect the humoral system often have
lineage-specific transcription factors T-bet [now also denoted
an inability to form and/or maintain memory, resulting in
as T-box 21 (TBX21)], GATA binding protein 3 (GATA-3), retiincreased susceptibility to infections (1, 2). Similarly, the ability
noid-related orphan receptor ct (RORct) or forkhead box
to induce B-cell (and T-cell) memory is the foundation for
protein P3 (FOXP3) (1). T-cell-dependent antibody production
protective immunity generated by vaccines. Yet, despite the
is a critical component of the normal immune response, and
clinical relevance of B-cell memory, the mechanisms underlyTh2 cells were originally believed to be the predominant
ing
formation and function of memory B cells remain elusive.
source of B cell help because of their production of IL-4, a
Various questions have been posed about B-cell memory.
cytokine known to be involved in B cell proliferation as well
What signals and genetic networks are required for its
as Ig class switching (1).
formation? How do memory B cells respond more rapidly
Subsequently, IL-21 was identified as a T -derived, type I,
and robustly during a secondary response?h What maintains
four-a-helical bundle cytokine that was critical for plasma cell
the population for long periods of time and, on the flipside,
generation as well as isotype switching (2) and normal Ig
what prevents exhaustion of the population? Although many
production (3), consistent with IL-21 being a Th2-specific cymolecules have been identified to be important
for the
tokine (4); however, other data indicated that IL-21 had Th1formation, maintenance and regulation of germinal center
like properties as well (5).
(GC) responses (reviewed in ref. 3), thus impacting
on the
More recently it became clear that the CD4+ T cells involved
quality and quantity of B-cell memory, these fundamental
in germinal center (GC) formation and function—denoted
questions remain unsolved.
T follicular helper cells (TFH cells)—were distinct from any
In the past decade, studies on B-cell memory in non-disease
of these previously identified subsets. These TFH cells
states have had three foci: gene expression studies, utilization
of gene-deficient animals to study the roles of genes expressed
during humoral responses and the formation of memory
subsets. In particular, recent studies have provided a more
in-depth characterization of T-independent (TI) formation
of B-cell memory (4–6) and the function of murine IgM
memory B cells (7, 8). The identification of multiple routes
expressed high levels of the chemokine receptor CXCR5
to memory B-cell formation has led to the idea that memory
[chemokine (C–X–C motif) receptor 5], allowing them to home
can be formed in ‘layers’, reminiscent of how evolution of the
to and be retained by the lymphoid follicle, where contact with
immune system has been described (9). In this review, we exantigen-primed B cells led to B cell proliferation, isotype
amine recent data demonstrating that memory B cells are
switching and somatic mutation of the Ig repertoire (6, 7).
formed in response to either TI or T-dependent (TD) stimuli.
Gene microarray analysis revealed that follicle-localized
CXCR5+ Th cells had a very distinctive transcriptional profile
that distinguished
these cells
Th1 or Th2 cells, with highMemory
B-cell formation
in from
TD responses
level IL-21 and B-cell CLL lymphoma-6 (BCL6) messenger
During a primary TD humoral response, antigen-stimulated
RNAs (mRNAs) (5), both of which are now considered hallB cells interact with activated T cells and other accessory
marks of TFH cells (6).
cells, resulting
in the formation of foci of short-lived plasma
IL-21 is a type I cytokine that signals via a specific recells (PCs), GC-independent ‘early’ memory cells or a GC
ceptor protein, IL-21R (8, 9), and the common cytokine
reaction, which can last a number of weeks before subsiding
receptor c chain, c , which is shared by the receptors for
(reviewed in ref. 9).c Within the GC, B cells undergo rounds
IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 (10); cc is mutated in
of division and affinity maturation, in which antibody
affinity
humans with X-linked SCID (11). IL-21 signals in part via
increases due to somatic hypermutation (SHM). Class switch
STAT3 (signal transducer and activator of transcription 3)
recombination (CSR) from IgM to IgG, IgA or IgE can occur,
(12), with actions on a wide range of lineages, including
although these processes can also occur outside a GC.
T cells, B cells, NK cells and dendritic cells (10). Specifically,
Eventually, high-affinity mutants are+ selected and
IL-21 can promote the expansion of CD8 T cells, is critical
differentiate into memory B cells or long-lived PCs (LLPCs).
for normal Ig production by B cells, can inhibit dendritic cell
During a secondary response, memory B cells differentiate
function and, interestingly, can be pro-apoptotic for B cells
rapidly into high-affinity plasmablasts, thus clearing the
and NK cells (10). Whereas IL-21 was first identified as
infection more quickly than the primary response.
REVIEW
Correspondence to: W. J. Leonard; E-mail: [email protected]
Correspondence to: K. L. Good-Jacobson, Immunology Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade Parkville,
Received
25 September
2009, accepted
30 October 2009
Victoria
3052,
Australia; E-mail:
[email protected]
2404 B-cell
memory
B-cell
memory
Memory B-cell subsets
The memory B-cell population in higher vertebrates is heterogenous (3). Subsets in both humans and mice can be
clearly identified by different Ig isotypes (e.g. IgM or classswitched isotypes) (7, 8, 10–12), and IgM memory B cells
and IgG memory B cells have been shown to be intrinsically
different (13). However, there are also less distinct differences, such as the levels of expression of different surface
proteins (e.g. co-stimulatory factors) (14, 15) that may reflect
the different experiences of each cell during the primary
response (3). In these latter studies, memory B cells can be
categorized into different subgroups based on cell surface
markers, and this could be correlated to precursor
frequency and mutation rate (but not to class switch) (15).
Other groups had previously identified heterogeneity
within the memory B-cell population (14–19) in both humans
and mice. For example, Cooper et al. have identified a
tissue-specific population of memory B cells in humans,
identified by the expression of FCRL4 (17, 18).
Finally, atypical memory B-cell populations found in HIV
and malaria patients have high expression of inhibitory
receptors, the presence of which is correlated to defective
function of the humoral system in these patients (20, 21).
Taken together, these studies suggest that the memory
population may be subdivided based on origin and function.
Interestingly, many gene-deficient mice and immunodeficient patients that lack productive GCs have cells that
resemble memory cells, but the population appears to have
an incomplete phenotype, such as few mutations, inadequate
affinity maturation or no class-switched isotypes (reviewed in
ref. 1, 3). These studies have revealed many genes that are
important for different phases of the GC response—i.e. formation, magnitude or resolution—affecting output of the GC and
thus the quality and quantity of the memory population but
not whether the memory population exists.
As a result, the definition of a memory B cell has become
contentious. Some researchers have made a priori assumptions based on observations of the cells that have been found
to persist in mice and man; i.e. the precursor cell of a canonical memory B cell is a GC cell, and therefore, its Ig must be
class switched and mutated. Thus, the main sources of
contention are whether IgM and/or low-affinity early memory
B cells, which can be found in the absence of a GC [or
paucity of GCs; (1, 3, 22–24)], can be defined as memory
cells. Similarly, TI B cells have not traditionally been considered as canonical memory B cells. We will focus this review
on the recent in vivo research into what might be regarded
as non-canonical memory formation.
TI memory
TI antigens can be TI type I (TI-I; for soluble antigens) or
TI-II (where antigen is cell-bound). Recently, various groups
have described LLPCs and memory-like cells formed during
TI responses in mice. First, LLPCs can be generated to TI-II
antigens, which secrete protective antibody from both the
secondary lymphoid organs (25) and the bone marrow
(4, 5). These LLPCs can either be IgM-secreting or be IgGsecreting; however, in at least one study, TI LLPCs secreted
lower amounts of antibody compared with LLPCs generated
during a TD response (4).
Unlike ‘conventional’ B cells (B2 cells), B1 cells were
thought to self-renew in the periphery, to be TI, to express
IgM but not to form memory cells; B1-a and B1-b subsets
have been described but it is not clear exactly how mouse
B1-a/B1-b subsets relate to the human equivalents.
Alugupalli et al. (26) demonstrated that mouse B1-b cells
give rise to an IgM-expressing B-cell population that persists, controls Borrelia hermsii infection and can confer
protection on transfer, suggesting that these are in fact
memory cells. Obukhanych and Nussenzweig used (4-hydroxy-3-nitrophenyl)-acetyl (NP)-Ficoll, a TI-II antigen, to
generate cells that persisted for many months post-immunization (6). When these cells were adoptively transferred
into naive hosts, they rapidly divided, although it is unclear whether they generated a burst of plasmablasts. Interestingly, both these groups confirmed older studies
demonstrating that serum Ig, specifically class-switched
Ig, inhibits the proliferation of TI memory cells (27, 28).
It remains unclear whether the B1-b memory population is
continually proliferating or whether, once generated, these
cells have an intrinsic survival advantage. There were some
differences between these studies. For example, in response
to NP-Ficoll, the memory population contains both IgG+ and
IgG cells (6), whereas in the study by Alugupalli et al., the
B1-b memory population was only IgM+ (26). Furthermore,
it is unclear if the precursor cells that respond to NP-Ficoll
are of B1 or B2 origin or both, or even whether aborted GCs
were generated (29).
In sum, both these studies (6, 26) demonstrate that immunity
formed during a TI response can be conferred when
transferred into naive hosts and that these ‘recall’ responses
are inhibited by serum Ig. However, it appears that this is
a quantitative rather than qualitative attribute; thus, it is as yet
unexplored whether these cells have an intrinsic advantage—as happens with TD memory in vivo and IgM and IgG memory
in humans (1, 13, 30, 31)—to respond more rapidly and robustly compared with naive B cells. Thus, it is clear that at
least TI-II antigens can form B-cell memory, although it is different to TD memory in regards to its longevity, secretion and
phenotype.
TD IgM memory B cells
Memory B cells that retain IgM on their surface have been
shown to exist in both mice (32) and man (1, 10–12). The
identity of these cells in humans is contentious, with some
groups identifying them as memory based on their functional
and molecular similarity to IgG memory and others
suggesting that they are ‘circulating’ marginal zone (MZ)
B cells (33) (splenic MZ B cells are generally mature, IgMexpressing and non-recirculating cells).
Two recent studies have investigated the origin, function
and persistence of murine IgM memory cells during a TD
response (7, 8). First, Weill et al. utilized a mouse encoding
a reporter for activation-induced cytidine deaminase expression to track cells that have been activated during an immunization with sheep red blood cells (7) (a classical TD
antigen). Taking this a step further, Jenkins et al. immunized
B-cell
memory4053
B-cell
memory mice with PE (a fluorescent TD antigen) and thus were able
to track antigen-specific cells throughout the response (8).
Taken together, both groups (7, 8) confirm that IgM
memory can be formed, and there are qualitative differences
between IgM and IgG1 memory. The two main findings
were, first, that IgM memory persists longer than IgG1
memory and, second, that class-switched memory B cells
differentiate rapidly into plasmablasts during a secondary
response, whereas IgM memory B cells had a slower
turnover rate and were less likely to participate in a secondary response in the presence of serum Ig (8). These IgM
memory B cells were less mutated than IgG memory B cells,
paralleling the IgM+CD27+ memory B cells found in healthy
people. Weill et al. proposed the concept of ‘layers’ of
memory (7), describing the existence of IgM memory and
IgG memory, as well as their proliferating precursors within
chronic GCs.
Thus, it appears that IgM memory B cells can be generated in both TI and TD responses and in the presence of
different adjuvants. Although TI and TD IgM memory cells
may qualitatively differ and/or have different precursors, they
have overarching characteristics regardless of the response.
The population can persist for months in vivo in mice, they
divide and confer protection when transferred into naive
recipients and are inhibited by serum Ig. Hence, it was
concluded that IgM memory B cells are important for persistence of the population, whereas IgG memory B cells are the
frontline responders. It is still unclear whether these murine
populations are equivalent to IgM+CD27+ memory B cells
found in humans, although Obukhanych and Nussenzweig
suggest that the inhibition by IgG is an important regulatory
mechanism in humans, highlighted by the fact that immunodeficient patients that do not generate IgG display hyperIgM syndrome (6).
Can subsets inform memory biology?
It could be proposed that the presence of memory subsets
answers some long-standing questions about memory B-cell
biology. Arguably, the three most important questions regarding memory biology are (Q1) how is the population
maintained over long periods of time, sometimes for the life
of the host; (Q2) what are the mechanisms underlying rapid
and robust secondary responses and (Q3) how are memory
B cells formed? We will discuss these recent papers within
the context of the first two questions.
The data presented in papers by both Weill and Jenkins (7,
8) suggest that IgM memory B cells may maintain the memory
population (Q1). Both papers demonstrate that IgM memory
B cells persist for longer periods of time than IgG memory
B cells—in fact, the same number of IgM memory cells is
maintained after an initial decrease during the resolution of
the primary response (8), whereas IgG memory B cells diminish in number over time. It is important to note that all these
studies are in mice, and therefore, it is difficult to directly
compare how long these cells may be maintained in humans.
Despite this, the data in these papers suggest that it may be
IgM memory B cells that maintain the memory population.
On the other hand, these data do not explain how a qualitatively better response is generated, beyond the known
abilities of canonical IgG memory B cells [Q2; (34)] as
murine IgM memory B cells do not have enhanced response
kinetics over naive B cells in vivo (8). It is important to note
that, in contrast, human IgM memory B cells have an
intrinsic advantage over IgM+ naive B cells with respect to
proliferation, co-stimulation, time taken to first division and survival (13, 30, 31); therefore, it is likely that there are
modifications in addition to expression of IgG rather than IgM
that account for enhanced secondary responses. In mice,
however, IgM memory B cells appear to have only two main
advantages over IgM+ naive B cells: an increase in number
over naive B cells and a higher-affinity B-cell receptor. Would
this be enough to induce rapid and robust secondary
responses after the eventual loss of IgG memory B cells?
On the flipside, the presence of IgM memory B cells may
be why the memory B-cell population is not exhausted
during a secondary response—although they are poor
responders in the presence of serum Ig, in the absence of
it, they can generate secondary GCs and replenish the IgG
memory compartment.
Although these studies do not reveal the molecular mechanisms underlying the formation of memory B cells, they
raise an important question: are there multiple independent
pathways to becoming B-cell memory (Fig. 1)? Or are the
different ‘types’ of memory (TI, IgM memory and early memory) in GC-deficient conditions intrinsically related? As Weill
et al. suggest, have we formed layers of memory over time?
Evolution of memory B cells
Protection, defined as the ability to produce a heightened
response to a previously seen infection, has been identified
in lower vertebrates, such as bony fish and amphibians
[tables summarizing data for secondary responses in vertebrates can be found in (35–37)]. For example, repeated
immunizations of trout have demonstrated that successive
responses induce heightened antibody levels compared
with the primary response. It has even been shown that
invertebrates, such as the bumblebee, are able to clear secondary infections more rapidly and with specificity (38).
Therefore, it is likely that a memory-like cells exists in lower
vertebrates and several invertebrates.
The protective antibody responses observed in lower
vertebrates do not show an increase in affinity compared with
the primary response. Unlike higher vertebrates that can regulate body temperature (homeotherms), poikilotherms do not
have the ability to form GCs (36). Yet, lower vertebrates have
transcription factors that have homology to those that regulate
B-cell differentiation in higher vertebrates, such as Bcl-6 and
Blimp-1 (39–42). Although the series of evolutionary events
that occurred in order to form GCs are unclear, it appears to
at least correlate with enhanced T-cell responses (and
thereby T-cell help) (43, 44) that occurred upon the increase
and regulation of body temperature (36) and the existence of
secondary lymphoid organs with complex organization and
the presence of follicular dendritic cells (reviewed in ref. 37).
Evidence of affinity maturation and selection appears with
GCs in higher vertebrates (36, 37) explaining why secondary
antibody responses in lower vertebrates are not of higher
affinity than the primary response.
4406 B-cell
memory
B-cell
memory
Fig. 1. Layers of memory. (A) Evolution of memory B-cell attributes. In some invertebrates and lower vertebrates, heightened secondary
responses have been detected, suggesting immune memory. Ig class switching and SHM have been detected in Xenopus. These traits were
found in animals that do not have GCs, which appeared relatively late in the evolutionary tree. With the addition of secondary lymphoid organs
and GCs, came affinity maturation and selection, leading to the canonical TD memory seen in humans and mice today. (B) Different pathways to
memory. In addition to TD memory [e.g. canonical GC-derived class-switched memory cells derived from follicular (FO) B cells], there are various
subsets of memory that have been described in both humans and mice. Shown are memory cells and their possible precursors, demonstrating
the complexity of determining lineage relationships. A different presentation of memory B subsets (C) demonstrates that different types of
memory have a layering of traits associated with the function of canonical TD memory, as seen with the evolution of memory B cells in
invertebrates and vertebrates over time (A).
Humans with immunodeficient diseases that affect GC
development, as well as lower vertebrates, similarly do not
form fully functional humoral responses (as discussed in
detail in ref. 45). Various GC-deficient or GC-defective mice,
such as those that lack Bcl-6, ICOS or IL-21 (22–24), are still
able to produce early memory-like cells, as can B1-b cells
in mice. Interestingly, B cells in lower vertebrates can undergo SHM in the absence of a GC. The amphibian
Xenopus, for example, contains B cells with somatic
mutations (46); however, because there is a lack of evidence
for affinity maturation in secondary responses in this
species, it appears that these somatic mutants are not
expanded and selected into the pool of persisting cells.
Similarly, patients with mutations in Cd40L (47) or Sh2d1a
(48) that have a paucity of GCs still have B cells that
undergo SHM, generating mutated IgM+ cells with a memory
phenotype. B cells in these patients can class-switch in the
absence of a GC, as can those in lower vertebrates such as
Xenopus (which switch to IgY) (46). Therefore, the cellular
machinery for SHM and CSR, normally associated with
affinity maturation and selection, appears to exist in B cells
in both lower vertebrates and patients that lack effective GC
responses. Taken together, investigation of primitive immunity demonstrates that B cells in lower vertebrates are able
to somatically mutate, differentiate into antibody -producing
cells and produce heightened protective responses, indicating that a memory-like population exists in these animals.
Are memory B cells an unintended consequence of infection in lower vertebrates? Memory B cells may have been
an intermediate state between naive B cells and PCs, i.e.
activated B cells that have undergone at least one round of
division but do not get signals to differentiate into a PC;
instead, they were able to escape death signals and revert
back to a ‘naive-like’ state. If so, at some point during evolution, the cells within this population acquired the ability to
persist. Evidence for an early induction of a memory state
post-activation has been observed in T cells: CD4+ T cells
that have been rested 2 days post-activation were observed
to have almost identical transcriptional profiles to those that
had been rested for 2 months (49).
Differentiation into PCs induces a large change in transcriptional networks. In contrast, naive and memory B cells
have very similar transcriptional profiles. While no ‘master
regulator’ of memory B-cell differentiation has been found,
B-cell
memory4075
B-cell
memory the differences in transcription consist of a number of
changes in cell cycle regulators, as well as ligands and
receptors that allow interaction with T cells (13, 30, 50, 51).
Similarly, upon activation, B cells integrate signals delivered
via surface receptors, leading to a genetic re-programing
that allows cell cycle and differentiation. Taken together, we
hypothesize that an activated B cell has the ability to differentiate into a memory B cell after only a few rounds of division,
and without the large changes in transcriptional networks
seen in GCs and PCs. GC responses were an addition to the
lineage relationship of naive and memory B cells that further
honed memory B-cell qualities. Once GCs were part of the
microenvironment, these cells were then able to go into a GC
‘state’ and undergo affinity maturation and selection. Memory
B-cell evolution can therefore be split into two stages, separated into the ability to produce a cell that can persist to provide protection and the acquisition of qualities that further
enhance the efficiency of secondary responses.
Evolution of mechanisms that regulate the humoral
response was necessary for stable GC function and have in
turn shaped the characteristics of the memory B-cell population. Within the GC, regulatory mechanisms provided by
Fas–Fas-L, PD-1–PD-L and limiting the amount of T-cell help
are vital in shaping the quality and quantity of the memory
population (22, 52–55). This is evident in mice lacking molecules important for a fully functional GC—rarely does the
ability to form a memory cell become completely disrupted;
however, the quality and quantity of the memory population
are different to that present in a control animal (reviewed in
ref. 3). The characteristics attributed to memory that are
attained within the GC, such as selection of high-affinity
mutants, are layered over other the characteristics required
for persistence. Heterogeneity within the immune system
may therefore reflect the importance of layering of attributes
of the memory population, both during the immune response
and over time.
Moving forward
There are of course questions that remain unanswered. Are
human IgM memory B cells counterparts of B1 or B2 memory in mice? Why is there a difference in longevity and
responses of IgM and IgG memory B cells? Is this difference
governed by intrinsic differences, and if so, are they at the
genetic or epigenetic level? In particular, research into histone
modifications that shutdown cell cycle to allow differentiation,
or alternatively to allow quick transcription of genes during
a secondary response, may reveal the answers to the
questions that still consume the memory field.
Conclusions
Adaptation is required for survival—this is the main tenet of
evolution. Thus, it would be advantageous for a naive B cell to
be structured in such a way that it is able to differentiate into
PCs, GCs or memory B cells, with extrinsic factors and epigenetic modifications influencing the fate of the activated B cell.
When the humoral adaptive system is deconstructed into
its components—i.e. the ability to respond to and clear foreign antigen, the ability to produce antibody, the ability for
a population of antigen-specific cells to persist and the
ability of these cells to respond to and clear the immunizing
antigen more rapidly during secondary responses—it
becomes clear that during evolution, the qualities and subsets of memory B cells routinely studied in mice and humans
have been layered over the more primitive structure that
originally existed. Genetic and epigenetic changes that
allowed persistence of the memory population, and thus
induced protection, were beneficial when selective
pressures were applied. Therefore, evolution has resulted in
the continual selection of traits that enhance the main
function of the immune system—to protect the host.
Funding
This work is supported by National Health and Medical
Research Council (NHMRC) Australia program grant to
D.M.T. (356202) and project grant to K.L.G-J (1022458).
K.L.G-J and DMT are supported by an NHMRC Biomedical
Research Fellowship and an NHMRC Research Fellowship,
respectively.
Acknowledgements
We thank Jennifer Walker for critical reading of this review. Note
added in proof: While in proof, an article was published in Journal of
Experimental Medicine (Taylor et al., 2012 Journal of Experimental
Medicine, DOI: 10.1084/jem.20111696) demonstrating that IgM
and class-switched memory B cells can be generated through
a GC-independent pathway.
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