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Upon
antigen recognition, naïve T cells have the capacity to differentiate into a
multitude of lineages with distinct effector and memory functions. T cell
receptor stimulation, costimulation, and cytokines induce transcriptional
program changes that critically regulate T cell proliferation, differentiation
and survival. While effector T cells mediate an efficient adaptive immune
response to primary antigen encounter, long-lived memory T cells are
responsible for rapid response to subsequent antigen counters. Both CD4 and CD8 T cells have the capacity to
form memory, however CD8 T memory cells are critical mediators of sustained
anti-tumor immunity. Memory CD8 T cells can be classified into several subtypes
based on their tissue-homing capacity, self-renewal capability and effector
recall responsiveness. Better understanding of the transcriptional programs
that regulate the generation and maintenance of T cell subsets, particularly T
memory subsets, may have significant implications in the development of
cellular therapies that achieve long-lasting anti-tumor effector function.
INTRODUCTION
During immune
response, naïve T cells possess a stunning capability to produce distinct
subsets of effector cells and memory T cells [1-7]. Although effector T cells
are armed to efficiently eliminate targets such as pathogens and tumor cells,
they are short-lived cells that undergo massive apoptotic contraction during
late stages of the effector phase [8-10]. Unlike effector T cells, memory T
cells are long-lived cells that undergo homeostatic survival in the absence of
a specific antigen. Upon re-encounter with the specific antigen, memory T cells
rapidly acquire effector functions and undergo clonal expansion to produce
large numbers of effector T cells, thereby providing protection against
secondary infections [1-3,5,11-15]. Thus, effective protective immunity against
infection and tumors requires the collective effort of heterogeneous lineages
of T cells.
Targeted
antigen specificity is a fundamental characteristic of the T cell response.
Both the initial activation of naïve T cells and the effector phases of T
cell-mediated elimination are triggered by recognition of the antigen by T cell
receptors (TCRs) presented on the surface of T cells [3,16]. Upon activation by
antigen-presenting cells (APCs), naïve T cells are triggered through TCR
signaling that induces cell-intrinsic transcriptional program changes.
Costimulatory signaling amplifies these programs to facilitate T cell
proliferation and expansion, while cytokines and notch ligands induce
differentiation of these activated T cells into distinct lineages of effector
cells [17-24]. Changes in these transcriptional programs are characterized by
the amount, location, and interaction of transcription factors that are
critical for T cell proliferation, differentiation, and survival.
Differentiation of T cells into effector subsets is regulated by master
transcription factors such as T-bet, Eomes, GATA3, RORγt, and Foxp3. This
regulation is complex and involves feedback mechanisms as well as overlapping
contributions from other transcription factors [17,18]. Transcriptional
programs can be further modified over time by stimuli present in the
environments where T cells execute their function. Transcriptional regulation
by Id3, Foxo1, T-bet and Eomes also significantly contributes to memory
formation and maintenance [25-27]. This review will discuss the impact of
transcription factors in regulating T cell heterogeneity and highlight exciting
findings from recent studies of transcription factors in regulating memory T
cells.
T Cell
Heterogeneity and Nomenclatures
The discovery
and dissection of the functional differences between effector and memory T cell
subsets have significantly advanced our understanding of the mechanisms
controlling the development of T cell heterogeneity. Prior to activation by
APCs, both CD4 T cells and CD8 T cells are designated as naïve and are
maintained in a quiescent state. Following activation, T cells undergo
programmed proliferation and differentiation, producing multiple lineages of
effector T cells based on the production of distinct effector molecules
[18,28]. Activated CD4 T cells can differentiate into distinct lineages of
effector cells (Figure 1), such as T helper-1 (Th1), Th2 and Th17 and
regulatory T cells (Tregs). Th1 CD4T cells are characterized by production of
interferon-g (IFN-g), whereas Th2 CD4 T cells secrete interleukin-4
(IL-4), IL-5 and IL-13 [18,20,29]. Th17 CD4 T cells are characterized by their
capacity to produce high amounts of IL-17 and IL-21 [18,28]. CD4 T cells can
also differentiate into Tregs, which can repress inflammatory T cells through
the production of IL-10 and TGF-b1 [30]. CD4 T cells may also differentiate
into other subsets such as T follicular helper cells (Tfh) [31] and Th9 cells
[32,33]. Tfh primarily reside in B-cell follicles and contribute to humoral
immunity [31]. Th9 cells, which display an interesting plasticity, may act with
Th2 in inflammatory responses or display immunosuppressive function through
production of IL-10 [32.34,35]. Activation of naïve CD8 T cells mainly induces
the generation of cytotoxic lymphocytes (CTLs) that produce IFN-g and
cytotoxic molecules such as granzyme B (GZMB), perforin (PRF1), and Fas ligand
(FASL). CD8 CTLs are capable of direct cell-mediated killing of target cells
[5,6].
CD4 and CD8 T
cells both possess the ability to form immunological memory through
differentiation into a population of antigen-specific memory T cells that
persist throughout the lifetime of an individual after resolution of
inflammation [17, 36, 37]. Following re-encounter with a specific antigen,
memory T cells can quickly expand and elaborate effector function, thus
providing the immune system with long-term protection against secondary antigen
encounters. Memory CD8 T cells are heterogeneous populations and have distinct
capabilities in the context of providing long-term protection against tumor
formation. They can be broadly classified into four subsets based on their
tissue homing capacity, self-renewal capability, effector recall responsiveness
and surface phenotype (Figure 2): effector memory T cells (TEM),
central memory T cells (TCM), resident memory T cells (TRM),
and stem cell-like memory T cells (TSCM) [3,8,38-44]. TEM express
low levels of CD62L and CCR7, allowing them to circulate and preferentially
home to non-lymphoid tissues. TCM express CD62L and CCR7,
restraining their homing to lymphoid tissues. TRM predominantly
reside in the local non-lymphoid tissues, such as the brain, mucosa, lung and
skin [7,39]. TRM express CD69 and CD10, surface markers, which
distinguish them from TEM [7,45-48]. Finally, TSCM are
a memory cell subset expressing a naïve cell-like phenotype of CD44lowCD62LhighSca-1highCD122highBcl2high.
They possess the ability to differentiate into all subsets of memory CD8 T
cells and effector cells, while maintaining self-renewal capabilities [41,42].
Immunological memory mediated by CD8 and CD4 T cells is critical for prolonged
protection against antigen reencounter and tumor formation (Figure 3).
The functional complexity of effector and memory subsets characterize T cell
heterogeneity. Transcription factors, which critically regulate differentiation
into these subsets, play a fundamental role in programming the diverse
functions of T cells, which collectively contribute to a comprehensive immune
response.
Transcription
Factors and Distinct Lineages of CD4 T Cells
Dozens of
transcription factors critical for the generation of distinct lineages of
effector and memory T cells have now been identified [18,49]. Seminal studies
have demonstrated that these transcription factors are important for
maintaining the plasticity and stability of effector CD4 T cells
[18,28,29,50,51].
Th1 cells. Th1 CD4 T cells are important in mediating
protection against pathogens and tumor cells. Importantly, Th1 cells also play
a critical role in mediating various types of inflammation, such as type I
diabetes, graft-rejection of transplanted organs, and graft-versus-host disease
(GVHD), a complication of allogeneic hematopoietic stem cell transplantation
[18,52-54]. Several transcription factors have been found to regulate CD4 Th1
cell differentiation, including T-bet, Eomes, Runx3, activator of transcription
(Stat) 1 and Stat4 [18,28]. These factors cooperate to direct Th1
differentiation and to maintain the stability of differentiated Th1 cells.
T-bet is a
master regulator of Th1 differentiation, with loss of T-bet leading to
dramatically impaired production of Th1 cells during immune response. T-bet
expression was found to be strongly dependent on signal transducer and Stat1,
rather than on IL-12–dependent Stat4. Stat1 is activated by IFN-g, and T-bet
expression further induces IFN-g production by differentiating cells,
thereby amplifying T-bet expression and upregulating the expression of IL12Rβ2
[17,18]. CD4 T cells expressing high levels of IL12Rβ2 respond to IL12 produced
by APCs, thus ensuring selective expansion of T cells differentiating towards
Th1 effector function [17,18]. Stat4, which is induced by IL-12, is also
positively regulated by IFN-g [55]. Activated Stat4 supports Th1
differentiation by further inducing the expression of IFN-g, IL12Rβ, and T-bet
[56,57]. The transcription factor Runx3 is upregulated upon CD4 T cell
stimulation and also functions to amplify T-bet and IFN-g expression [58].
Furthermore, overexpression of Runx3 in vitro has been shown
to promote and accelerate Th1 differentiation [59].
Recent studies
have demonstrated that several other transcription factors, such as Zbtb7b
(also called Th-POK) and the Notch effector RBP-j/CSL, may also contribute to
the development of distinct lineages of effector CD4+ T cells
[20,21,28,60,61]. Eomesodermin (Eomes), another member of the T-box protein
family, is dispensable for antigen-induced Th1 cell development and function,
but may induce IFN-g production in CD4 T cells under non-polarizing
conditions when T-bet is not upregulated [62]. Thus, T-bet and Eomes cooperate
with each other to promote IFN-g production under different conditions.
Th1 cell differentiation occurs in parallel with the repressed
production of inappropriate cytokines such as IL-4 and IL-17 [18]. It is
through this mechanism that T-bet suppresses the development of both Th2 and
Th17 cells. T-bet prevents Th2 cell differentiation by inhibiting transcription
of IL-4, a signature Th2 cytokine, and by inhibiting the function of Gata3, a
master regulator for Th2 cell differentiation [63]. T-bet can also interact
with the promoter of RORC (which encodes RORγt, a master regulator of Th17) to
inhibit Th17 cell differentiation [64,65].
Th2
cells. Th2 cells primarily mediate
the adaptive immune response to parasitic protozoa and helminths [18,66,67].
Th2 cells are also able to drive B cells to produce several subclasses of IgG
and IgE antibodies. Furthermore, cytokines produced by Th2 cells activate
eosinophils and mast cells, causing inflammatory damage to tissues including
the lung and airway [68-70]. Gata3 and Stat6 are transcription factors
critical for the induction of Th2-associated cytokines (i.e., IL-4, IL-5 and
IL-13) [63]. GATA3 conditional knockout studies showed that GATA3 expression is
required for Th2 differentiation [71]. In differentiated Th2 cells, continuous
GATA3 expression is essential for maintaining production of IL-5 and IL-13, but
not IL-4. Furthermore, Gata3 has a dual function in the repression of Th1
differentiation by antagonizing T-bet expression in proliferating CD4 T cells
[63,71]. Stat6 is the major signal transducer in IL-4-mediated Th2 cell
differentiation and is critical for the production of IL-4 in CD4 T cells, as
demonstrated by the failure of STAT6-deficient CD4 T cells to develop into
IL-4-producing cells in vitro. Stat6 activation is also necessary
and sufficient for inducing high expression levels of GATA3 [18,28,72-74].
Th17
cells. The Th17 subset is
characterized by production of IL-17 and is important in mediating responses to
pathogens. Th17 cells have also been implicated as potent effectors of
autoimmune diseases such as Crohn’s disease, ulcerative colitis, rheumatoid
arthritis and psoriasis [18,50,65,75]. Th17 cell differentiation requires two
key transcriptional regulators: RORγt and Stat3. Deficiency of RORγt leads to
profound interruption of Th17 cytokine expression, whereas forced expression of
RORγt induces the production of IL-17A and IL-17F, both of which mediate
pro-inflammatory responses, but differ in the type and site of inflammation
[76,77]. Stat3 plays an important role in Th17 cell differentiation by inducing
RORγt and by directly binding to IL-17A and IL-17F promoters [50,65,75]. In
addition to positive regulation of Th17 differentiation by RORγt and Stat,
transactivation of RORγt by Runx1 is also critical for induction of the Th17
subset [63,78,79]. In contrast, the Runx1/FOXP3 interaction or Runx1/T-bet
collaboration leads to the interruption of Runx1-mediated transactivation of
RORC, thereby repressing Th17 differentiation [63,78,79].
Treg. There are two major classes of CD4 Treg cells,
including natural Treg (nTreg) and inducible Treg (iTreg), both of which sustain
immune system homeostasis by mediating self-tolerance and modulating
inflammation. nTregs develop in the thymus during thymopoiesis, and are
therefore termed thymic Tregs, whereas iTregs can be induced in peripheral
tissues during immune responses [80,81]. Both subsets require the
expression of the transcription factor Foxp3, which may be used
to characterize these subsets [80]. Mutations of the FOXP3 gene can
prevent Treg development, causing the fatal autoimmune disease IPEX [82].
iTreg3, a novel subset recently identified in mice and humans, is noteworthy
because unlike previously identified subsets, it does not express Foxp3.
Furthermore, this subset mediates immunosuppressive effects via IL-35 rather
than the canonical cytokines IL-10 and TGF-β [83,84]. Several elegant papers
have recently reviewed Treg biology and it will therefore not be discussed here
[85,86].
Transcriptional
Regulation of Effector and Memory CD8 T Cells
Effector
differentiation and expansion. Upon APC activation, antigen-specific CD8 T cells undergo a highly
reproducible pattern of clonal expansion and differentiation. TCR and
costimulatory signaling together with cytokines activate transcription programs
important for regulating effector differentiation and expansion. T-bet and
Eomes have been shown to function as master regulators for promoting CD8
effector T cell differentiation and function [26,87,88]. CD8 T cells lacking
both T-bet and Eomes lose CTL identity and abnormally differentiate into
IL-17-producing CD8 T cells that cause excessive neutrophil infiltration and a
lethal inflammatory syndrome during LCMV infection. During acute response,
T-bet and Eomes have cooperative and partially redundant effects on promoting
CTL formation by inducing the expression of the cytotoxic molecules perforin
and GZMB in activated CD8 T cells [87,88]. Importantly, effector CD8 T cells
expressing high levels of T-bet are prone to terminal differentiation and
become KLRG1hi short-lived effector cells (SLECs) [9]. During
chronic infections, effector CD8 T cells expressing high levels of Eomes are
susceptible to exhaustion and ultimately lose their ability to control chronic
infection [89]. Interestingly, this demonstrates that the phenotype, function,
and long-term fate of effector CD8 T cells are acutely sensitive to the
relative ratio of T-bet and Eomes [89], yet the regulation of this ratio in
activated T cells remains largely unknown.
Blimp-1
contributes to a transcriptional program that enhances CTL functions, such as
migration to sites of inflammation and production of IFN-g and GZMB
[90-93]. Animals with a CD8 T cell-specific deficiency in Blimp-1 have an
impaired ability to clear influenza virus due to poor recruitment of
virus-specific CD8 T cells to the lungs [93-95]. However, high expression of
Blimp-1 promotes terminal differentiation of CD8 SLECs and induces exhaustion
of chronically activated CD8 T cells [91-94]. Thus, Blimp-1 has multiple roles
in regulating effector T cell responses.
IFN regulatory
factor 4 (Irf4) regulates CD8 T cell differentiation and expansion during acute
infection [96,97]. While Irf4 is dispensable for early activation of CD8 T
cells, it is important for effector differentiation and expansion [96,97]. Irf4
simultaneously promotes the expression and function of Blimp-1 and T-bet along
with repressed genes that mediate cell cycle arrest and apoptosis. Selective
deletion of IRF4 in peripheral CD8 T cells impairs antiviral CD8 T cell
responses [96]. Irf4 also influences the expansion of SLECs at the peak time of
infection, but has no effect on the rate of T cell contraction. This effect of
Irf4 is associated with increased expression of Eomes and Tcf1 in CD8 T cells
[96].
Several other
transcription factors regulate the expansion of effector CD8 T cells. Inhibitor
of DNA binding 2 (Id2), which is a member of the inhibitor of DNA-binding
family, is required for the survival of effector CD8+ T cells
during early expansion phase [27,98]. More recent studies suggest that Id2 is
especially important for the formation of terminal KLRG-1hiTEFF [99].
As compared to Id2, Id3 promotes the survival of TEFF later
during effector expansion, in particular when effector cells develop into
memory cells [27]. Enforced expression of Id3 has been shown to be sufficient
to restore SLEC survival and enhanced recall responses [100]. These data
suggest that while both Id2 and Id3 are critical to the survival KLRG-1hiSLECs,
their effects occur at different stages of effector expansion. Although the
precise mechanisms by which Id2 and Id3 regulate the survival and expansion of
effector cells remain largely unknown, available data show that their
pro-survival effects are likely associated with their regulation of
anti-apoptotic genes (e.g., Bcl, Serpinb9 and Bcl2l11) and genomic stability,
respectively [27,98-100].
Recent studies
have demonstrated the importance of the transcription factor Bcl11b in
antigen-dependent clonal expansion and cytolytic activity of CD8 T cells [101].
BCL11b deficiency was shown to have no impact on effector differentiation, but
caused significantly decreased proliferation of antigen-activated T cells later
during clonal expansion phase. BCL11b deficiency in CD8 T cells also leads to
deregulation of CD8 co-receptor and Plcg, both of which contribute to the impaired
responsiveness of activated T cells [101]. It will be interesting to
investigate how these transcription factors are coordinated to regulate the
survival and expansion of effector CD8 T cells in the environment where
effector cells reside and execute function.
Memory
formation and maintenance. Memory CD8 T
cells are derived from proliferating T cells during the clonal expansion phase
and may be classified into four different subsets (Figure 2): TCM,
TEM, TRM, and TSCM [3,8,38-44].
Identifying the differentiation pathways for heterogeneous memory T cell
subset development following naïve T cell activation has been an area of
active investigation [7]. In mice, these cells can be classified based on
surface phenotype (e.g., CD62L, CD4, CD127 and KLGR-1) [3,5,7]. Genome-wide
studies reveal that TSCM express gene programs that resemble,
but are distinguishable from naïve T cells, thus being considered less
differentiated than other subsets of memory cells [102]. As compared to TCM,
TEM express more genes associated with effector function,
proapoptotic signaling, and certain chemokines [103-105]. This correlates with
the difference in effector function between TCM and TEM;
the former lack immediate effector function and are less differentiated, while
the latter have immediate effector function and are further differentiated. A
progressive differentiation pathway based on signal strength and/or extent of
activation has been proposed, with naïve T cells as the least differentiated
cells, followed by TSCM, TCM and TEM cells
in a differentiation hierarchy (Figure 3) [42,43106]. Together, these
memory T cell subsets function as precursors for TEFF.
Some studies
indicate that arresting effector differentiation of antigen-specific CD8 T
cells enables them to differentiate into memory T cells. For example,
antagonizing IL-2 with IL-21 has been shown to increase the generation of TCM [107,108]
and induction of Wnt/b-catenin signaling using inhibitors of
glycogen-synthase-kinase (GSK)-3β or Wnt3a protein induces the generation of TSCM [42].
GSK-3β inhibition mimics Wnt signaling by promoting accumulation of β-catenin,
the molecule that forms complex with Tcf1 and Lef transcription factors for
regulating gene expression [42]. Tcf1 mediates signaling downstream of the Wnt
pathway and promotes the development of memory T cells [42]. Mice lacking Tcf7
gene, which encodes Tcf, have a more differentiated effector/effector memory
cell phenotype (i.e., CD44highCD62Llow) [109,110].
The forkhead-box
O (Foxo) family of transcription factors is a well-defined target of Akt. Akt
phosphorylation at conserved sites of Foxo proteins triggers their nuclear
exclusion and inactivation. Foxo1 and Foxo3 are the predominant Foxo members
expressed within immune cells [111]. Foxo1, in particular, controls TCM responses
to infection [25] and is highly expressed in memory-precursor T cells. Foxo1
binds to and regulates expression of Tcf7 and Ccr7, which have critical
functions in TCM formation and trafficking. Deletion of Foxo1
causes defective secondary, but not primary, CD8 T cell responses to Listeria
monocytogenes in mice [25]. Thus far, Foxo3 has no established role in
mediating recall response of CD8+ T cells, as demonstrated by an
antigen-specific in vivo study [112].
Id3 plays an
important role in regulating the transition of activated CD8 T cells into
effector cells and memory cells [27,100,113]. Studies using mice expressing a
reporter for Id3 have shown that Id3+ memory precursors occur
before the peak of T cell population expansion or upregulation of cell surface
receptors associated with memory potential [27]. It is likely that Id3 is
important for preserving proliferating CD8 T cells with memory potential early
during priming and expansion phase. Loss of Id3 leads to defective formation of
long-lived memory cells [27]. Ectopic expression of Id3 reportedly enhances
recall response capability of tumor-reactive CD8 T cells and increases the
production of memory precursor cells in mice [100]. High expression of Id3
preferentially guides the transition to memory cells, whereas low expression of
Id3 leads to differentiation into effector cells [27].
Reducing the
abundance of pro-differentiation transcription factors T-bet and Eomes may
potentiate the generation of memory T cells. During acute response, CD8 T cells
lacking both T-bet and Eomes lose CTL identity, and generate KLRG1low memory
precursor cells, including both TSCM and TCM.
However, their effector recall response capability is impaired upon reencounter
of the antigen [114]. In addition, in memory CD8 T cells, Eomes sustains
homeostatic survival and proliferation of memory cells through regulating
IL-2Rβ expression [26]. Loss of Eomes leads to decreased IL-2Rβ expression,
which is required for IL-15-mediated signaling and homeostatic proliferation of
memory cells in the absence of antigen. Mice lacking Eomes reportedly have
impaired turnover of long-term memory cells, largely due to reduction of IL-2Rβ
[26]. Furthermore, despite promoting the generation of memory T cells,
reduction of Eomes and T-bet levels simultaneously leads to diminished effector
capability. New approaches are needed to investigate if Eomes and T-bet might
play an important role in regulating recall responsibility of memory T cells.
Recall of
effector functions. It is
noteworthy that the mechanisms for effector function recalled in memory cells
differ from that of the primary effector response. For example, Id2 is required
for the survival and expansion of effector cells generated during primary
response, but is dispensable for reactivation of effector function by memory
CD8 T cells [99]. Blimp-1-deficient effector CD8 T cells are reportedly
generated and showed some reduction in expression of effector molecules
[91-93]. Both TEFF and TEM have decreased
proliferative capacity when rechallenged by their specific antigen. In
contrast, loss of Blimp-1 leads to a faster development of TCM and
has no impact on recall response of memory T cells to become effector cells
[92]. It is likely that other transcription factors are required for regulating
the recall response capability of memory T cells. Alternatively, reactivation
of effector function by memory cells may involve a multitude of mechanisms
rather than a single transcription factor.
Interplay
between Cytokines Signals and Transcription Factors in Memory Cells
Emerging
evidence indicates that T cell heterogeneity is dictated during the antigenic
priming phase and can be further modified in response to environmental stimuli.
TCR ligation and inflammatory cytokines such as IL-12 and IFN-g upregulate
T-bet in activated CD4 and CD8 T cells [26,88,115]. Some studies report that
APC-derived Notch ligand activation of Notch signaling in T cells upregulates
their expression of T-bet and Eomes and results in differentiation of effector
T cells [19,21,23]. Notch signaling is also known to
be important for induction of Gata3 and RORγt in Th2 and Th17 cells,
respectively [21,23,24,116,117]. Thus, both the degree and type of inflammatory
stimulation serve to establish higher levels of lineage-specifying
transcription factors (e.g., T-bet, Eomes, GATA3, RORγt) and induce distinct
lineages of effector cells [9].
Recent studies
suggest that inflammatory cytokines regulate expression of Id2 and Id3 in
activated CD8 T cells. Using Id2-YFP and Id3-GFP reporter mice, Goldrath and colleagues
assessed the effect of cytokines on CD8 T cell expression of Id2 and Id3 during
antigen-driven immune response [27]. While in vitro treatment
with IL-2, IL-12 or IL-21 resulted in increase of Id2, in vivo experiments
further confirmed the effect of IL-2 signaling on Id2 upregulation [27].
However, inactivation of IL-12 did not affect the expression of Id2. Thus, it
is likely that IL-2 is a critical factor upregulating Id2 in vivo,
whereas IL-12’s effect may be redundant in vivo when IL-2 is
available [27]. In contrast, IL-12 lowers Id3 expression in antigen-activated
CD8 T cells in an in vivo experimental model, suggesting that
IL-12 induction of effector differentiation leads to the down-regulation of Id3
[27]. The observation that IL-12 upregulates T-bet in activated T cells and the
increasing effector pool [9] suggests that it may be useful to determine how
cytokines and transcription factors act in concert to modulate the expression
of Id2 and Id3 in T cells for effector differentiation and memory formation.
T Cell
Heterogeneity And Protective T Cell Immunity
To achieve
efficient protective T cell immunity against infection and tumor cells,
antigen-specific T cells are partitioned into subsets of memory T cells with
distinct homing, self-renewal and effector recall potential. Adoptive cellular
immunotherapy (ACT) is emerging as a potentially curative therapy for patients
with advanced cancer. A major caveat of ACT is the observation that
antigen-experienced T cells at distinct differentiation states may have
different antitumor activity in vivo [42,102,118-120]. For
example, as compared to TEM, TCM are less
differentiated [2-4,6,8,121,122], have greater ability to proliferate and
produce functional effector T cells [2-4,6,8,121,122], and show increased
antitumor activity relative in many experimental studies [42,118-120,123,124].
Our recent studies [41] and others [42] have identified a population of
antigen-experienced TSCM in mice [42]. As compared to TCM and
TEM, TSCM have a greater ability to inhibit tumor
progression. TSCM have also been discovered in humans and have
superior antitumor immunity in humanized mouse models [43]. Recent studies by a
separate group further confirmed the potency of human TSCM against
minor histocompatibility antigens (miHAs) in mediating potent antitumor
activity in humanized mice [125]. Therefore, both TSCM and TCM serve
as source for the total pool of memory cells and effector cells. They both have
the high degree of cell plasticity and lowest degree of effector function, with
TSCM exhibiting these characteristics more potently
[43,106,120]. The development of novel approaches which activate memory cells
and generate secondary effector cells may have significant implications in
augmenting the efficacy of ACT.
The importance
of T cell heterogeneity is reportedly important for T cell immunity against
chronic infection [89]. Using both human and mouse chronic infection models,
Wherry and colleagues have demonstrated that differential expression of T-bet
and Eomes in distinct subsets of virus-specific CD8 T cells cooperatively
maintain the pool of antiviral CD8 T cells during chronic viral infection [89].
During chronic infection phase, antiviral CD8 T cells expressing high levels of
T-bet are slowly proliferating cells, but undergo rapid proliferation in
response to the specific antigen and produce terminal progeny cells expressing
high levels of Eomes. The absence of T-bet causes a shift toward
Eomes-expressing terminal progeny cells and impedes the control chronic viral
infection. Deletion of Eomes results in failure to control chronic infection
due to the reduction of terminal effector cells [89]. Thus, both the
T-bet-dependent and Eomes-dependent subsets of antiviral CD8 T cells
cooperatively contribute to an effective protective immunity against chronic
infection.
CD4 T cells
also provide effective protection against tumor and chronic infection. Recent
studies suggest that CD4 T cells not only promote CD8 T cell function, but also
play a direct role in tumor elimination [126-130]. The manner in which
CD4 T cells mediate anti-tumor immune response depend on the generation of both IFN-g-producing progeny and cytolytic
effector cells that can destroy tumor cells [127,128]. Notably, recent evidence
suggests that CD4 Th17 cells help CD8 T cells to mediate long-term anti-tumor
immunity [131,132]. Thus, efficient protection immunity against tumor and
pathogen reflects collective efforts of differential subsets of
antigen-specific T cells.
Modifying T
Cell Heterogeneity for Tumor Immunotherapy
One of the main
barriers to improving the efficacy of ACT is ensuring the preservation of T
cell self-renewal, which ensures the continuous production of progeny capable
of eradicating tumor after adoptive transfer into patients [42,43,106,120].
Considerable efforts have been made to improve methods used for ex vivo expansion
of tumor-reactive T cells for ACT. An approach under active evaluation involves
the growth of cells under conditions that enable ex vivo proliferation
while limiting differentiation (Figure 4). The addition of
GSK3-b inhibitors into cultures has been shown to reduce effector
differentiation and increase the frequency of both TSCM and TCM [42,43].
This subset of TSCM has greater ability than other subsets of
memory T cells to control the growth of established tumors upon adoptive
transfer [42,43].
TCR, IL-2
receptor and IL-12 receptor signaling have all been demonstrated to stimulate
the PI3K/Akt signal transduction pathway [133-135]. Several studies suggest
that PI3K/Akt is critical for proliferation and differentiation of activated
CD8 T cells. Increased activation of Akt by IL-12, expression of a
constitutively active form of Akt and deletion of Foxo1, have all been shown to
promote the formation of KLRG1hieffector cells [5,9,136]. A recent
study shows that inhibiting the Akt pathway leads to generation of highly
potent miHA-specific CD8 T cells ex vivo [125]. These
Akt-inhibited CD8 T cells showed superior expansion potential upon removal of
the Akt inhibitor, which results in a superior antitumor effect in a humanized
mouse model [125]. Akt inhibition can also enhance persistence of
tumor-infiltrating lymphocytes after adoptive transfer into an immunodeficient
animal model and augment antitumor immunity of CD8 T cells [137].
Cytokines such
as IL-15 and IL-21 can sustain T-cell proliferation while limiting excessive
differentiation, exhaustion, and senescence. T cells cultured in IL-15 display
a TCM-like phenotype and gene expression profile, and have greater
anti-tumor function in mice than T cells cultured in IL-2 [138,139]. IL-21
modulates the differentiation of activated T cells and results in development
of a population of cells characterized by a TSCM phenotype
[108,140]. Human T cells cultured in IL-21 retain the ability to release IL-2
and express markers associated with a minimal differentiated phenotype (e.g.,
CD45RA, CD28, CD27, IL7Ra and CD62L) [108,140,141]. In a mouse model of
melanoma, T cells derived from IL-21 cultures demonstrated markedly enhanced
anti-tumor activity compared with cells grown in the presence of other
cytokines [108].
The
CD27-dependent pathway of T-cell expansion has therapeutic potential to enhance
the efficacy of ACT. CD27 is highly expressed on the surface of naïve CD8 T
cells [142-145]. Activating CD27 by soluble CD70 promotes cellular expansion of
CD8 T cells in the absence of IL-2 without causing significant effector
differentiation [142,143,145]. This effect of CD27 signaling resulted in
increased cell cycling and survival that was mediated in part by upregulation
of IL-7Ra on the T cell surface [142,143,145]. Data from animal experiments
also indicate that CD27-null CD8 T cells have impaired primary and secondary
expansion in mice challenged by influenza and polymavirus. Finally, CD27 is
reported to mediate the generation of antigen-experienced CD8 T cells with
memory traits [142,145,146]. Further preclinical studies using ACT models are
necessary to evaluate the validity of CD27-dependent expansion of T cells as a
feasible approach to improve the efficacy of ACT for patients with advanced
cancer.
CONCLUDING
REMARKS
This review has
highlighted the significant progress that has been made in understanding how
transcription factors regulate the development of T cell heterogeneity. A
multitude of transcription factors coordinate their activities to orchestrate
distinct transcriptional programs that direct the differentiation and
maintenance of a functionally diverse group of T cell subsets. The upstream
molecular pathway(s) involved in orchestrating the expression of these
subset-specific transcriptional programs remain a critical unresolved question.
The continued exploration of transcriptional control of T cell heterogeneity will
have broad implications in identifying novel pathways that may be targeted to
create therapies for autoimmune diseases, chronic infections and complications
involved with transplantation, including graft rejection and GVHD.
In addition, a
greater understanding of transcriptional programs controlling terminal
differentiation and memory formation will have an immediate impact on T
cell-based anti-tumor therapies such as ACT. During ACT, a strong antitumor
effect in patients with advanced cancer can be achieved by transfer of large
amount of cytolytic effector T cells. Current in vitro methods
used to expand tumor-reactive T cells are ineffective in maintaining a
population of minimally differentiated T cells while generating sufficient cell
numbers. The predominant obstacle to retaining this population is the
fundamental coupling of clonal expansion and effector differentiation. This
coupled expansion and differentiation impairs the generation of memory T cells
that are able to persist and replicate to elaborate effector function for
eliminating tumor in vivo following adoptive transfer. Further
exploration of the molecular mechanisms whereby T cells closely link expansion
and differentiation will lead to new strategies to improve the efficacy of
cancer immunotherapy.
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