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Immunology and Cell Biology (2014) 92, 34–39
& 2014 Australasian Society for Immunology Inc. All rights reserved 0818-9641/14
www.nature.com/icb
REVIEW
Regulatory mechanisms that control T-follicular helper
and T-helper 1 cell flexibility
Amy S Weinmann
Following antigenic stimulation, CD4 þ T cells have the potential to differentiate into a number of specialized effector cell
subtypes. To date, much progress has been made in defining the basic molecular mechanisms that regulate initial helper T-cell
differentiation decisions. Emerging research in the field is now uncovering more complexity in the series of events that control
helper T-cell commitment decisions than was previously appreciated. During the commitment process, helper T cells need to
integrate both signals derived from the T-cell receptor and from the surrounding microenvironment. These external signals are
then translated into internal changes in gene expression potential to ultimately define the functional characteristics of the cell.
In this review, this topic will be discussed from the perspective of T-follicular helper (Tfh) and T-helper type 1 (Th1) cell
differentiation. The focus will be on examining how the cytokine environment is perceived by signaling through signal transducer
and activator of transcription (STAT) family proteins to initiate fate choices. The activities of STAT proteins are then in turn
translated into changes in the molecular balance between B-cell lymphoma 6 (Bcl-6) and T-box expressed in T cells (T-bet),
the helper T-cell lineage-specifying transcription factors that regulate Tfh and Th1 effector cell differentiation, respectively.
Collectively, the knowledge of the molecular pathways that regulate Tfh and Th1 commitment have provided insight into the
relationship between these two specialized helper T-cell subtypes and the potential for flexibility in their gene programs.
Immunology and Cell Biology (2014) 92, 34–39; doi:10.1038/icb.2013.49; published online 1 October 2013
Keywords: Tfh; Th1; T-bet; Bcl-6; STAT; helper T cells
In multicellular organisms, progenitor cells have the capacity to
differentiate into specialized cell fates. Conserved lineage-specifying
transcription factor families are required to precisely regulate gene
expression program transitions to initiate unique cell fate choices.1
Developmentally controlled signaling events can tip the balance of
these factors to promote commitment towards an individual cell fate
choice at the expense of an alternative lineage.2–4 In the immune
system, multipotential progenitor cell populations commit along
individual fate pathways as environmental conditions signal the cell
to change the composition of lineage-specifying transcription factors,
ultimately resulting in the development of the full complement of the
unique cell types that make up a functional immune system.
The mechanistic principles that mediate developmental transitions
continue to operate when lineage committed cells, such as CD4 þ
T cells, further differentiate into functional effector fates. In contrast
to the stable commitment pathways that mediate lineage differentiation decisions, emerging research suggests that the transitional events
that promote more refined functional effector states retain a greater
degree of flexibility than is observed with a true developmental
decision.5–8 This is an especially important new area of research
exploration in the field of CD4 þ T-cell differentiation, because
the degrees to which specialized CD4 þ T-cell subtypes remain
responsive to their microenvironment impacts how we approach
immunotherapy and vaccination strategies.6,9 To date, much effort
has been invested into defining the mechanisms that regulate the
commitment of CD4 þ helper T cells into specialized functional
subtypes.10–14 The emphasis of research efforts are now shifting
towards uncovering the mechanistic reasons why these commitment
events allow specialized CD4 þ T cells to remain flexible and respond
to changing environmental conditions.7,15–17 In this review, this topic
will be examined from the perspective of the molecular mechanisms
that translate changing environmental conditions into specialized
T-follicular helper (Tfh) and T-helper type 1 (Th1) gene programs
and how these mechanisms provide insight into the potential for
helper T-cell flexibility.
ACTIVATION OF NAIVE CD4 þ HELPER T CELLS
It is important to first highlight the type of events that create the
milieu of regulatory factors that will be present in the cell and will
have the potential to impact the commitment decision of naive
CD4 þ helper T cells towards a specialized effector fate. The first event
that occurs, which changes the composition of regulatory pathways
activated in a cell, is the antigen-dependent engagement of the T-cell
receptor (TCR) along with costimulation. Signaling through the TCR
and costimulation activates a number of regulatory pathways,
including the induction of NFAT and AP-1.18 Current research
Department of Immunology, University of Washington, Seattle, WA, USA
Correspondence: Dr AS Weinmann, Department of Immunology, University of Washington, Box 358059, 750 Republican Street, Seattle, WA 98195, USA.
E-mail: [email protected]
Received 12 August 2013; revised 28 August 2013; accepted 29 August 2013; published online 1 October 2013
Tfh and Th1 flexibility
AS Weinmann
35
efforts are focused on defining how the TCR repertoire contributes to
the differentiation potential of specialized helper T-cell subtypes.
Recent studies have suggested that TCR intrinsic properties
predispose the cell towards initiating either a Th1 or Tfh
program.19,20 Interestingly, the strength of TCR signaling, as
determined by the duration of TCR engagement with peptide–major
histocompatibility complex II (MHCII) complexes, pushes a cell
towards a fate choice, with strong TCR signaling promoting Tfh
differentiation.19 Taken together, this means that a clonal population of
cells is predisposed towards initiating a Th1 or Tfh program based on
the characteristics of the TCR, but that the pathogen burden can also
influence cellular differentiation as well. This is because antigen
concentrations can change the dwell time between the peptide–
MHCII complexes and the TCR, which will impact the strength of
TCR signaling.19 Mechanistically, it is currently unclear which series of
molecular events that occur downstream of TCR signaling are required
to differentially induce the specialized effector cell programs. This will
be an exciting new avenue of research to pursue in future studies.
REGULATORY PATHWAYS CONTROLLED BY ENVIRONMENTAL
CONDITIONS
Following antigen-dependent activation, the differentiation of a CD4 þ
T cell into an effector fate is next dependent on the environmental
conditions the CD4 þ T cell encounters after activation. Most often,
the encounter with a specific type of pathogen will cause the innate
immune cells in the environment to initiate a somewhat prototypic
cytokine response to the pathogen.21–23 For instance, the conserved
components of bacteria and viruses (for example, pathogen-associated
molecular patterns) are recognized by pattern recognition receptors,
such as the Toll-like receptors, that cause innate immune cells to
secrete a specific complement of cytokines and chemokines.21,24 The
cytokine environment created by the innate immune response thus
represents the first dominant microenvironment that influences
CD4 þ T-cell effector differentiation. Therefore, depending on the
characteristics of the pathogen, this initial microenvironment will
usually induce a defined effector cell program designed to combat a
specific type of pathogenic insult.
However, the environmental milieu that a CD4 þ T cell is exposed
to is more complex than merely accounting for the factors secreted by
the initial ‘hard-wired’ response of innate immune cells to the
invading pathogen, especially when considering the functional lifespan of effector and memory cells.25,26 For instance, the
microenvironment can be influenced by competing factors such as
another infection or a chronic condition that results in prolonged
systemic changes in the environment. The temporal changes during
the course of an immune response also influence specialized CD4 þ
T cells. Collectively, this means that as long as the cells remain
responsive to an environmental signal, the new microenvironments
that the cells encounter throughout the course of an infection will
have the potential to change the functional characteristics of the
CD4 þ T cells. These are particularly interesting points to think about
in the context of the potential for flexibility in the Tfh-like cells that
are found in circulation versus germinal center (GC) Tfh cells located
in the follicle, or in regards to effector versus memory Th1 cells
circulating in different anatomical locations.27–30
REGULATING THE EXPRESSION PATTERNS OF
LINEAGE-SPECIFYING TRANSCRIPTION FACTORS
An important aspect of how specialized CD4 þ T-cell gene expression
programs are established is through the regulatory activities of
developmental lineage-specifying transcription factor families.
Lineage-specifying transcription factors have evolved conserved
mechanistic activities that promote the transition from one cell
program to another. Many times these transcription factors utilize
mechanistic activities that alter the epigenetic state of select target
genes.31–33 In addition, they also possess the dual ability to either
activate lineage-specific genes or, alternatively, repress genes involved
in opposing cellular states.34,35 In true developmental lineages, the
lineage-specifying transcription factors promote cellular transitions
that are permanent, resulting in the development of a new cell fate.36
Previously, the paradigm in the field was that the differentiation of
CD4 þ T cells into specialized subtypes was a stable developmental
fate choice.37,38 However, experimental observations have discovered a
much more complicated picture, uncovering complex and flexible
gene expression patterns in specialized helper T cells that are
inconsistent with a solely stable fate model.6,7,39 This concept will
be highlighted by examining how changing environmental signals,
mediated via signal transducer and activator of transcription (STAT)
proteins, modulate the molecular balance between the opposing
helper T-cell lineage-specifying transcription factors T-box expressed
in T cell (T-bet) and B-cell lymphoma 6 (Bcl-6), and how this in turn
regulates flexibility in the Th1 and Tfh gene programs.
SENSING THE ENVIRONMENT THROUGH THE STAT FAMILY IN
TFH AND TH1 DIFFERENTIATION
Many of the cytokines responsible for the differentiation decisions
that promote specialized CD4 þ T-cell effector subtypes modulate the
activity of STAT proteins.40,41 This transcription factor family serves
to translate the external cytokine environment into internal events
that control many aspects of cellular differentiation, including
regulating the expression of helper T-cell lineage-specifying
transcription factors.41–43 The helper T-cell lineage-specifying
transcription factors then orchestrate another series of events, often
still in cooperation with STAT proteins, to create a predominantly
specialized effector cell program. Detailing how the STAT family
mechanistically regulates aspects of Tfh and Th1 gene programs
powerfully illustrates the relationship between these two specialized
subtypes and the events that contribute to the potential for flexibility.
The complexity of how the STAT proteins translate the cytokine
environment into functional changes in specialized CD4 þ T cells is
reflected by the nature of the specific versus redundant pathways that
upregulate their activities, and then also by the specificity and
redundancy in the downstream gene expression programs that are
regulated by each family member.40 This concept is quite evident in
studies examining Tfh cell differentiation.44 Here a number of elegant
studies have defined the roles for STAT1, STAT3 and STAT4 in
positively regulating aspects of Tfh cell differentiation in response to
interleukin-6 (IL-6), IL-21 and IL-12, as well as an inhibitory role for
STAT5 in response to IL-2.44–48 These studies are clarifying the
environmental conditions that promote Tfh differentiation and the
role for STAT proteins in this process. It is now clear that there is
functional redundancy between cytokine signaling pathways and the
STAT family member activities that promote Tfh differentiation,
leading to the concept that multiple signaling pathways have the
potential to initiate a Tfh response.44 Another intriguing aspect of
these studies is that the same STAT signaling pathways that
promote Tfh differentiation are also involved in the development of
alternative specialized CD4 þ helper T-cell subtypes in other
situations.44,49 This means that the cellular context for STAT family
member activity is important for defining the specialized CD4 þ
T-cell gene expression program that will be established in response
to an environmental signal.
Immunology and Cell Biology
Tfh and Th1 flexibility
AS Weinmann
36
These concepts become evident when comparing the role for
individual STAT proteins in Tfh versus Th1 differentiation, as well as
in examining mouse versus human Tfh cells. Recently, several
comprehensive reviews were published addressing how STAT proteins
regulate Bcl-6 induction and Tfh differentiation.44,50,51 The focus here
will be on highlighting the STAT-protein-regulated events that have
the potential to influence aspects of either Tfh or Th1 differentiation.
SENSING IL-6 AND INTERFERON-c THROUGH STAT1
The early research surrounding the STAT proteins focused on defining
how individual STAT family members are activated by different
cytokine microenvironments.49 This information was then integrated
into models highlighting the potential for unique STAT proteins to
predominantly drive the differentiation of individual specialized
helper T-cell responses.49 Recent research has provided a much
more complex view of this topic, with individual STAT family
members having roles in what had previously been thought of as
opposing helper T-cell fate decisions.44 An example of this is in the
role for STAT1 in both Th1 and Tfh cell differentiation. It has long
been recognized that the interferon-g (IFNg)-dependent upregulation
of STAT1 induces the expression of the Th1 lineage-specifying
transcription factor T-bet to promote the differentiation of the Th1
gene program.52–54 However, recent studies have revealed that IL-6
also activates STAT1, but in this context STAT1 promotes the
induction of Bcl-6 and the development of a Tfh phenotype.44,47
Thus, STAT1 is able to integrate a set of diverse environmental signals
to tip the balance of the cell towards either a Th1 or Tfh phenotype.
One of the interesting questions the field now faces is defining
mechanistically how STAT1 serves as a positive regulator for both the
Th1 and Tfh gene programs. Current data indicate that STAT1 is able
to promote the upregulation of either T-bet or Bcl-6 depending upon
the cellular context.47,53 A plausible hypothesis for how STAT1 can
achieve specificity in the differential regulation of T-bet or Bcl-6 is
that unique IFNg- or IL-6-dependent signaling events will induce a
specific composition of additional regulatory factors in the cell that
influences the final outcome of STAT1 activity. In this scenario, one
complement of factors induced in response to IFNg signaling will
favor the STAT1-dependent enhancement of T-bet expression,
whereas IL-6 signaling will favor a different complement of factors
to promote Bcl-6 expression. It is plausible to envision the possibility
for flexibility between the Th1 or Tfh pathways if different sets of
environmental conditions change the expression patterns of the
complementary factors present in the cell. In other words, given
that STAT1 serves as a conserved determinant for both T-bet and Bcl6 expression, dynamically altering the composition of the other
regulatory factors involved in selecting the lineage-specifying factor
will influence the downstream decision between the expression of the
Th1 and Tfh gene programs.
IL-12 SIGNALING INITIATES THE STAT4-DEPENDENT
REGULATION OF T-BET AND BCL-6
A series of studies in both mice and humans have shown that the IL12-dependent upregulation of STAT4 can promote the induction of
both T-bet and Bcl-6.48,55–57 Of note, this is in contrast to the
integration of different environmental signals (that is, IFNg or IL-6)
mediated by STAT1. In mice, immediately following the activation of
CD4 þ T cells, exposure to environmental IL-12 causes the
simultaneous induction of T-bet and Bcl-6 in a STAT4-dependent
manner.48 The co-expression of T-bet and Bcl-6 results in the dual
expression of IFNg and IL-21 by CD4 þ T cells. Interestingly, T-bet
eventually outcompetes Bcl-6 when IL-12 signaling persists, resulting
Immunology and Cell Biology
in the downregulation of Bcl-6 expression to low levels. This allows
for the predominance of a Th1 gene program at the expense of the
Tfh-like state.48 Although the resolution of the STAT4-dependent coexpression between T-bet and Bcl-6 favors T-bet in environments
with robust IL-12 conditions, it is possible that pathogenic insults that
induce a more blunted IL-12 response could have the capacity to
favor Bcl-6 over T-bet. In addition, if there are unique environmental
signaling events that contribute to the decision of whether STAT4
predominantly activates either T-bet or Bcl-6 expression,
encountering variations in these environmental conditions will
likely have the potential to create flexibility between the Th1 and
Tfh gene expression profiles later in the lifespan of the cells.
The studies associated with IL-12 signaling in human cells suggest
an even more prominent role for IL-12 in Tfh potential, creating a
more complicated picture concerning the dichotomy between Th1
and Tfh cells in the human setting.55–58 The current data indicate a
role for the IL-12-dependent induction of STAT3 and STAT4 in
promoting the sustained expression of IL-21 and Tfh cell
differentiation in human cells.56,58 This is in contrast to the
transient induction of IL-21-producing CD4 þ T cells in response
to environmental IL-12 observed in the murine setting.48 In addition,
data from patients with mutations in IL-12 receptor b1 have a
pronounced defect in Tfh cell development, also supporting the
conclusion that there is a substantial role for IL-12 signaling in the
generation of Tfh cells in the human setting.55 Intriguingly, a high
proportion of IL-21-producing cells also co-express IFNg, likely
reflecting the prominent role for IL-12 signaling in both IL-21 and
IFNg expression in the human setting.56 Together, these data raise the
possibility that human Th1 and Tfh cells may have an even greater
degree of interrelatedness and flexibility between their gene programs
due to the overlapping role for IL-12–STAT4 signaling in both
specialized effector cell outcomes.50 These findings also suggest that
additional regulatory factors that are not yet defined will have a
prominent role in influencing whether IL-12–STAT4 signaling will be
translated into a more T-bet-dominated Th1 gene program or a more
Bcl-6-centric Tfh gene program in human immune responses. Further
knowledge about the mechanisms that occur downstream of IL-12
signaling to tip the balance between T-bet and Bcl-6 to favor either
the Th1 or Tfh gene programs will provide new insights into the types
of environmental changes that will have the potential to influence
these outcomes.
IL-21 SIGNALING ENHANCES TFH DIFFERENTIATION
There are often feedback loops that reinforce gene expression
programs to create more stability in their phenotypes.38 IL-21 is an
important cytokine involved in the germinal center B-cell response, in
part, through its role in creating a positive feedback loop promoting
the GC response.59,60 Tfh cells secrete IL-21 and, in turn, IL-21
signaling in Tfh cells also promotes the expression of genes associated
with the Tfh phenotype.61,62 IL-21 signaling in Tfh cells
predominantly upregulates the activity of STAT3 and, to an extent,
STAT1, which then promotes the induction of Tfh-associated
genes.40,44,45 Intriguingly, both IL-6 and IL-21 promote the
activation of similar STAT family members and both have a role in
Tfh development.45 Functional redundancy has been a common
theme in the studies examining Tfh differentiation, with a large
degree of redundancy observed in both the cytokine milieu and in the
STAT family members that translate these environmental signals into
the induction of the Tfh gene program.45 It has been hypothesized
that this redundancy is advantageous because of the critical
Tfh and Th1 flexibility
AS Weinmann
37
importance for the antibody response in controlling diverse
pathogenic insults.44
IL-2 SIGNALING MODULATES THE BALANCE BETWEEN STAT3
AND STAT5 IN CD4 þ T-HELPER CELLS
STAT3 and STAT5 have been shown to have opposing roles in
regulating some classes of target genes.63 In the case of Bcl-6
expression, STAT3 has a role in activating Bcl-6 expression, while
STAT5 appears to be inhibitory towards Bcl-6 expression.15,46,64 This
is an important point because in cells maintained in Th1 polarizing
conditions, changes in environmental IL-2 have been shown to
modulate the relative association of STAT3 and STAT5 with the
Bcl-6 promoter.15 Notably, several independent studies have shown
that high levels of environmental IL-2, which promotes STAT5
activation, inhibits Bcl-6 expression and Tfh differentiation.15,46,65,66
Interestingly, effector and memory Th1 cells remain responsive to
environmental IL-2 conditions to create a scenario in which IL-2sensitive Bcl-6 expression changes have the potential to regulate
flexibility between the Th1- and Tfh-like gene programs.15
COMMONALITIES IN STAT FAMILY MEMBERS IN TH1 AND
TFH DIFFERENTIATION
The high degree of overlap between the STAT family members that
have roles in Tfh and Th1 differentiation is striking (Figure 1). As just
highlighted, recent research has shown that the STAT family members
once thought to have unique roles in Th1 development are also
involved in generating a Tfh gene program.44 This is quite evident
when considering the well-established required roles for STAT1 and
STAT4 in the induction and maintenance of T-bet expression to
promote Th1 cell development.49 As discussed above, several recent
studies now indicate that STAT1 and STAT4 also contribute to the Tfh
gene program.47,48,56 At least part of this role appears to be in
regulating Bcl-6 expression.44 In addition, it also appears that STAT4
directly contributes to the induction of a subset of Tfh signature
genes.48 Thus, STAT1 and STAT4 have roles in both the Th1 and Tfh
gene programs, with a prominent aspect of this in regulating T-bet
and Bcl-6 expression.
At present, it is not entirely clear how the context of activation
influences the activity of STAT proteins and the overall decision
within the cell to predominantly initiate a Th1 or Tfh gene program.
IFN
IL-6
STAT1
T-bet
Th1
IL-21
IL-12
STAT3
STAT4
IL-2
STAT5
Bcl-6
Bcl-6
T-bet
Bcl-6
Tfh
Tfh
Th1
Tfh
Figure 1 Cytokine signaling pathways that regulate Th1 and Tfh
differentiation. Regulatory pathways for each cytokine are highlighted with
different colors and the relative strength of the pathway is indicated by the
thickness of the arrow. The schematic illustrates that there is a significant
degree of overlap between the cytokine and STAT signaling pathways that
regulate both the Th1 and Tfh gene programs.
The milieu of other regulatory proteins present in the cell will have a
role in the commitment and stabilization of the effector cell phenotypes between Tfh and Th1 cells. In this line of thought, studies have
shown that basic leucine zipper transcription factor ATF-like (Batf)
and c-Maf are important for the differentiation of Tfh cells, whereas
H2.0-like homeobox (Hlx) has a role in Th1 cell responses.67–71 Thus,
the environmental context for the activation of these regulatory factors
will influence the commitment decision. It will be important to
determine what series of events are required for the expression of
these, and other, regulatory factors, because this may represent one of
the key selective events that define the phenotype of the cells.
Another intriguing possibility is that the cellular context, or the
receptor signaling strength leading to STAT protein activation, will
contribute to the selection of the downstream Th1 or Tfh gene
expression pathways that are activated in different circumstances. The
quality of STAT protein activation may be influenced by either the
exposure to different cytokines, or the relative strength of cytokine
signaling, impacting the overall composition of STAT protein activity
or family member selection. An example for how signaling strength
controls diverse outcomes is with the graded regulation of Bcl-6
expression in Th1 cells exposed to variable environmental IL-2
conditions.15 Here, the strength of IL-2 signaling is translated
through the relative induction of STAT3 versus STAT5 activity,
which then determines the expression levels for Bcl-6 in Th1 cells.
Therefore, changes in cytokine concentrations in the environment
have the potential to alter the balance between competing STAT
family members activities, which can then cause graded changes in
lineage-specifying transcription factors. The relative competing
activities between STAT3 and STAT5 are also likely to differentially
regulate the expression of additional target genes important in
establishing either the Tfh or Th1 phenotypes as well.
MOLECULAR BALANCE BETWEEN T-BET AND BCL-6 IN
TH1–TFH FLEXIBILITY
Modulating the expression of lineage-specifying transcription factors,
such as T-bet and Bcl-6, represents a powerful way to integrate realtime changes in the microenvironment, because these transcription
factors have the capacity to alter the underlying gene expression
program of the antigen-specific effector cells. In part, the nature of the
interplay between T-bet and Bcl-6 regulates both the commitment and
the potential for flexibility between specialized Th1 and Tfh subtypes.
Mechanistically, T-bet and Bcl-6 can physically interact to form a
complex in helper T cells.15,34 The properties of the interaction
between T-bet and Bcl-6 create a scenario in which T-bet is able to
control Bcl-6 activity when the balance of the two proteins favors
T-bet expression. This is because the DNA-binding zinc fingers of Bcl6 are required for the interaction with T-bet, whereas, in contrast, the
C-terminal domain of T-bet, but not its centrally located DNAbinding domain, is required for complex formation with Bcl-6.15 Thus,
T-bet–Bcl-6 complex formation will mask the DNA-binding domain
of Bcl-6, but the T-bet DNA-binding domain will still be exposed.15
This means that when the conditions in the cell favor T-bet–Bcl-6
complex formation, it will prevent Bcl-6 from accessing its own target
genes. However, as the DNA-binding domain of T-bet remains
available, T-bet can target the repressive capability of Bcl-6 to a
subset of its target genes to downregulate the expression of genes
involved in alternative helper T-cell fates.34,35 Mechanistically, this also
means that T-bet activity is dominant over Bcl-6, especially when there
is a higher ratio of T-bet to Bcl-6 in the cell. As noted above, both
T-bet and Bcl-6 expression is controlled by the activities of similar
STAT family members that are activated in response to changes in the
Immunology and Cell Biology
Tfh and Th1 flexibility
AS Weinmann
38
cytokine microenvironment of the cell. Therefore, the molecular
balance between T-bet and Bcl-6 can be fine tuned by changes in
the composition of STAT protein activities to effectively sense the
microenvironment and create new functional capabilities for the cell.
CONFLICT OF INTEREST
The author declares no conflict of interest.
ACKNOWLEDGEMENTS
INTEGRATING THE COMPONENTS THAT TRANSLATE THE
ENVIRONMENT INTO TH1 AND TFH EFFECTOR STATES
The emerging data in the field examining Th1 and Tfh differentiation
is providing new insight into the concept of either defining
specialized helper T-cell fates as stable lineages, akin to the T- and
B-cell fates, versus viewing them from the opposite end of the
spectrum as completely flexible cell populations that are defined by
the environment. The physiological answer appears to lie somewhere
in between these two extremes. Insight into this topic is being
extrapolated from the recent series of studies highlighted in this
review that have shown there is a similar composition of STAT family
members, and in some cases the same cytokine environmental
conditions, which are involved in regulating the expression of
T-bet and Bcl-6. This raises the possibility that the underlying gene
expression programs of Th1 and Tfh cells have a degree of relatedness
in their origin and also will remain responsive to similar environmental perturbations. Therefore, the decision for the functional
direction of the specialized helper T cell will involve the integration
of the conserved STAT signaling events, along with the composition
of other regulatory factors concomitantly activated in the cell, to alter
the balance between T-bet and Bcl-6. Notably, the cell maintains the
ability to dynamically respond to changes in the environment
because of the nature of these regulatory mechanisms.
One important question that arises from the recent findings
surrounding flexibility is how these same mechanisms can also account
for the stability in the specialized helper T-cell subtypes that is often
observed in the natural setting of the immune response.72 Here it is
helpful to view the stability versus flexibility of the cell as a gradient of
possibilities that is determined by the underlying mechanisms that
regulate these processes. For example, stability will be promoted by any
mechanistic event that makes it more difficult for a cell to respond to
changes in the microenvironment. This may include downregulating
receptors for cytokines and chemokines, altering the composition of
additional regulatory proteins that are found in the cell, or establishing
repressive epigenetic states surrounding the genes that are important
for alternative phenotypes.39,66,73 If many layers that promote stability
are built up in the cell, this may effectively ensure a highly stable
specialized functional subtype that becomes relatively impervious to
environmental changes. In contrast, the less layers of stability that are
embedded in the cellular phenotype, the more likely it is that the cell
will remain highly dynamic to respond to changes in the
microenvironment. Therefore, the observations characterizing both
stability and flexibility in specialized helper T-cell phenotypes in
different circumstances do not represent a contradiction, but rather
likely represent the number of barriers that are found within the cell
population at any given point in natural immune responses. As
discussed in this review, much information on this topic is already
available with regards to Tfh and Th1 cells, and this is guiding new
concepts in this area of study. In moving forward in the field, it will be
important to define more completely the mechanisms that create these
gradients of stability/flexibility, especially in relationship to the Tfh and
Th1 gene programs. In the context of Tfh cell activity, understanding
these principles may help with designing more efficacious vaccination
strategies by creating conditions that promote the generation of stable
Tfh cells and more robust antibody responses.
Immunology and Cell Biology
I would like to thank Ken Oestreich and members of the Weinmann lab for
helpful discussions. Research in the author’s laboratory is supported by grants
from the NIAID (AI061061) and the American Cancer Society (RSG-09-04501-DDC).
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