Regulatory T cells induced by B cells: a novel subpopulation of regulatory T cells
Chien and Chiang Journal of Biomedical Science
Regulatory T cells induced by B cells: a novel subpopulation of regulatory T cells
Chien-Hui Chien 1
Bor-Luen Chiang 0 1
0 Department of Medical Research, National Taiwan University Hospital , Taipei City 10002, Taiwan , Republic of China
1 Graduate Institute of Clinical Medicine, National Taiwan University , Taipei City 10048, Taiwan , Republic of China
Regulatory T cells play a crucial role in the homeostasis of the immune response. In addition to CD4+Foxp3+ regulatory T cells, several subsets of Foxp3- regulatory T cells, such as T helper 3 (Th3) cells and type 1 regulatory T (Tr1) cells, have been described in mice and human. Accumulating evidence shows that naïve B cells contribute to tolerance and are able to promote regulatory T cell differentiation. Naïve B cells can convert CD4+CD25- T cells into CD25+Foxp3- regulatory T cells, named Treg-of-B cells by our group. Treg-of-B cells express LAG3, ICOS, GITR, OX40, PD1, and CTLA4 and secrete IL-10. Intriguingly, B-T cell-cell contact but not IL-10 is essential for Treg-of-B cells induction. Moreover, Treg-of-B cells possess both IL-10-dependent and IL-10-independent inhibitory functions. Tregof-B cells exert suppressive activities in antigen-specific and non-antigen-specific manners in vitro and in vivo. Here, we review the phenotype and function of Foxp3+ regulatory T cells, Th3 cells, Tr1 cells, and Treg-of-B cells.
Regulatory T cells; Lymphocyte-activation gene 3; Programmed cell death protein 1; Inducible T-cell co-stimulator; Interleukin 10; Cytotoxic T lymphocyte-associated antigen-4; Treg-of-B cells
Regulatory T cells are a therapeutic strategy for immune
dysregulated diseases and a potential target for cancer
immunotherapy. In addition to CD4+Foxp3+ regulatory
T (Treg) cells, studies have emphasized the roles of CD4
+Foxp3- regulatory T cells, such as TGF-β-producing T
helper 3 (Th3) cells, IL-10-producing type 1 regulatory
T (Tr1) cells, and others. Accumulating evidence
demonstrate that naïve B cells possess the ability to promote
naïve CD4+ T cells into CD25+ Foxp3- regulatory T cells
with the expression of lymphocyte activation gene-3
(LAG3, CD223), inducible co-stimulator (ICOS, CD278),
programmed cell death protein 1 (PD1, CD279), and
glucocorticoid-induced TNFR family-related protein
(GITR). B-cell-induced CD4+Foxp3- regulatory T cells
exert the inhibition through both IL-10-independent and
cell-cell contact-dependent mechanisms, although they
also show IL-10-mediated suppression. Furthermore,
these B cell-induced regulatory T cells protect mice from
several immune disorders, including graft-versus-host
disease, experimental allergic asthma, collagen-induced
CD4+Foxp3+ regulatory T cells
Sakaguchi et al. demonstrated that CD4+CD25+ T cells
contributed to maintaining self-tolerance in a
nonantigen-specific manner [
]. Immune dysregulation,
polyendocrinophathy, enteropathy X-linked (IPEX)
syndrome is a recessive immune disorder. Reports showed
that IPEX is caused by mutations of FOXP3 gene, which
is orthologouse of the Foxp3 gene mutated in scurfy
]. Further studies demonstrated that Foxp3
expressed predominantly in CD4+CD25+ T cells than
CD4+CD25- T and CD19+ B cells. Moreover, retroviral
transduction of Foxp3 in naïve CD4+CD25- T cells
converted these cells toward Treg cells phenotype. Thus,
Foxp3 has been identified as the master transcription
factor of Treg cells [
Thymus-derived Foxp3+ regulatory T cells
In addition to Foxp3, thymus-derived CD4+CD25+Foxp3
+ regulatory T (tTreg) cells highly expressed Helios,
cytotoxic T lymphocyte-associated antigen-4 (CTLA4,
CD152), neuropilin-1, GITR, galectin-1, IL-10, and
granzyme B [
]. tTreg cells could be activated in an
antigenspecific fashion and exerted suppressive activity in a
non-antigen-specific fashion [
]. tTreg cells produced
many inhibitory cytokines, including TGF-β1, IL-10, and
IL-35, to downregulate immune responses [
Furthermore, tTreg cells exhibited cell-cell contact-dependent
suppression via latency-associated peptide (LAP) [
CD39 (ectonucleoside triphosphate
diphosphohydrolase1, ENTPD1) and CD73 (ecto-5′-nucleotidase) [
cytosolic cyclic adenosine monophosphate (cAMP) [
Reports showed that tTreg cells induced effector T cell
apoptosis via various pathways, including deprivation of
IL-2 and IL-7 [
], disruption of effector cell membrane
integrity by granzyme B [
], and the engagement of TNF-related
apoptosis inducing ligand (TRAIL)-death receptor 5
]. Additionally, tTreg cells inhibited effector
T cell activation via downregulation of costimulatory
molecules on DCs through CTLA4 [
] and LAG3
]. These studies indicate that tTreg cells are a
polyclonal population, and the above mentioned
complicated mechanisms result in maximal
immunosuppression during homeostasis.
Peripherally derived Foxp3+ regulatory T cells
Foxp3+ regulatory T cells induced in vivo are called
peripherally derived regulatory T (pTreg) cells and those
generated in vitro are called in vitro-induced regulatory
T (iTreg) cells [
]. Studies demonstrated that CD4
+Foxp3- T cells differentiated into Foxp3+CD25
+CD45RBlow anergic T cells with suppressive functions
in the presence of TGF-β1 in vitro as well as in vivo [
and rescue Foxp3-deficient scurfy mice [
]. In the
absence of tTreg cells, oral antigen administration induced
the generation of CD4+CD25+Foxp3+ regulatory T cells
in a TGF-β1-dependent manner [
lymphoid tissue CD103+ DCs played an important role
in the de novo conversion of naïve T cells into pTreg
cells, and retinoic acid facilitates that process [
Additionally, lung-resident tissue macrophages expressed
retinal dehydrogenases, and TGF-β1 promoted pTreg
cell induction under steady-state conditions [
Evidence has shown that the tumor environment
induced pTreg cell generation to escape immune
]. One report demonstrated that tTreg and
pTreg cells shared similar phenotypes, and neuropilin-1
serving as a surface marker to distinguish tTreg cells
from pTreg cells [
CD4+Foxp3- regulatory T cells
The most well-defined Foxp3- regulatory T cells are Th3
cells and Tr1 cells. Th3 cells have been identified as
TGF-β-producing CD4+LAP+ T cells exhibiting
TGF-βmediated suppression [
]. Tr1 cells have been
characterized by the higher production of IL-10 and
IL10-mediated suppressive functions [
T helper 3 cellsl
Th3 cells were first found in mesenteric lymph node
CD4+ T cells as single cell clones producing TGF-β1
after oral administration of self-antigen [
]. Oida et al.
found that primary purified CD4+CD25-LAP+ regulatory
T cells protected mice from T-cell-induced colitis in a
TGF-β1-dependent manner [
]. Tumor environment
CD4+CD25-CD69+Foxp3-LAP+ T cells expressed IL-2
receptor β chain, produced TGF-β1, and exerted
TGFβ1-mediated functional activity [
]. Gandhi et al.
showed that human peripheral CD4+LAP+Foxp3-CD69+
T cells exhibited TGF-β1- and IL-10-dependent
suppression in the periphery in healthy individuals [
Furthermore, human CD4+CD25+LAP+Foxp3- T cells in
colorectal tumors expressed LAG3 and exhibited
inhibitory functions through TGF-β1 and IL-10 [
]. To date,
the specific transcription factor for Th3 cells remains to
Type 1 regulatory T cells
The first study on Tr1 cells reported that naïve T cells
repeated stimulation with peptide-pulsed splenocytes in
the presence of IL-10 induced IL-10-producing CD4+ T
cells with suppressive ability and hypoproliferative ability
]. Akbari et al. demonstrated that bronchial DCs
promoted Tr1 cells in vitro in an IL-10-and ICOS/ ICOS
ligand (ICOSL)-dependent manner in the context of
nasal tolerance [
]. By microarray analysis Tr1 and Th0
cell clones, CD49b, LAG3, and CD226 have been
identified as the surface markers of Tr1 cells [
It has been shown that c-Maf transactivated IL-10
expression under CD4+ Th17 polarization conditions
]. Aryl hydrocarbon receptor (AhR) and c-Maf
facilitated IL-10 production in CD4+ T cells in an
IL-27dependent fashion [
]. Another study reported that
c-Maf, IL-21, and ICOS were essential for IL-27-induced
Tr1 cell generation . Consistent with these
observations, Awasthi et al. showed that CD4+Foxp3+ regulatory
T cell-educated DCs produced IL-27 and promoted Tr1
cell generation [
]. Nasal anti-CD3ɛ antibody treatment
induced the expression of IL-10, IL-27, and TGF-β in
nasal tolerogenic DCs, which further facilitated Tr1 cell
generation through c-Maf, IL-21, and AhR [
antigen treated tolerogenic Peyer’s patch DCs increased
the production of IL-10 and IL-27 and promoted the
induction of Tr1 cells [
]. Carrier et al. reported that
constitutive ectopic expression of GITR ligand (GITRL)
on MHCII+ APCs increased IL-27 production and
further upregulated the expression of c-Maf and IL-10 in
T cells [
In addition to cytokines, reports have demonstrated
that Tr1 cells could be induced by different proteins,
different APCs, and different types of T cells. Galectin-1
promoted IL-10 expression in CD4+ T cells in an
APCindependent pathway by binding to CD45 on T cells and
inducing the expression of c-Maf and AhR [
]. In vitro
activation of CD4+CD44hiFoxp3- T cells through
antiCD3/CD28 antibodies and IL-2 generated CD49b-,
LAG3-, c-Maf-, and AhR-expressing Tr1 cells [
et al. found that long-term stimulation of
lipopolysaccharide (LPS) conferred ICOSL expression in bone
marrow-derived mast cells through NF-κB, subsequently
promoting Tr1 cell development [
]. These reports
suggest that the generation mechanisms for Tr1 cells
consist of a fine-tuning program.
B cells in tolerance induction
B cells have been shown to have a role in the fine
equilibrium for immune tolerance. Genetically
B-celldeficient mice delayed recovery from experimental
autoimmune encephalomyelitis and suggested B cells might
contribute to immune modulation [
fragments expressed on B cell MHC class II sufficiently
delayed the onset and decreased the severity of arthritis
]. The role of B cells in oral tolerance has been
investigated because B-cell-deficient mice exhibit a defective
oral tolerogenic response characterized by lower levels
of IL-10 and TGF-β in the spleen and gut-associated
lymphoid tissues [
]. Gutgemann et al. showed that B
cells interacted with T cells at the B-T border in the
spleen after 4 h of oral administration of proteins [
Furthermore, orally antigen treated B cells have an
enhanced ability to induce CD4+ regulatory T cells in
]. Anterior chamber-associated immune
deviation was characterized by antigen-specific
downregulation of the immune response to antigen occurs in the
anterior chamber of the eye [
], and this phenomenon
was abrogated in the absence of B cells [
suggested that splenic B cells presented antigens derived
from ocular APCs and induced CD4+CD25+ regulatory
T cells via IL-10 and MHC class II [
evidence emphasize the role of B cells in the induction
and maintenance of self-tolerance.
There is accumulating evidence demonstrating that
specific B cell subsets modulate immune responses
named as regulatory B (Breg) cells by Mizoguchi et al.
]. Breg cells dampened immune responses though the
secretion of IL-10, TGF-β, directly interact with
activated CD4+ T cells, and the production of antibody that
neutralized harmful soluble molecules [
]. Several Breg
cells have been described in mice and IL-10-producing
Breg cells are the most widely studied [
produced by a variety of Breg cells suppressed inflammatory
cytokines and promoted regulatory T cell differentiation
]. These indicate that B cells contribute to the
maintenance of tolerance.
In addition, naïve B cells functioned as
antigenpresenting cells presented antigen and resulted in T cell
tolerance to antigen [
]. Raimondi et al. demonstrated
that adoptive transfer of antigen-presenting B cells four
times in a week lead to antigen-specific CD4+ T cells
tolerance independent of naïve or activated B cells [
Antigen-presenting follicular B, marginal zone B, and B-1a
cells rendered antigen-specific T cells hyporesponsiveness
without Foxp3+ Treg cells induction . One study
reported that B cells contributed to Treg cells homeostasis
and cooperated with Treg cells to ameliorate inflammation
]. These findings suggest that B cells play a role in
immune modulation and might through the manipulation
of CD4+ Treg cells.
B-cell-induced CD4+Foxp3- Treg-of-B cells
Naïve splenic B2 cells, peritoneal B-1a cells, and mucosal
Peyer’s patch B cells have been shown to induce CD4
+CD25+Foxp3- regulatory T cells, which named
Treg-ofB cells by our group, without additional cytokines or
]. Naïve splenic B cells and naïve
splenic CD4+CD25- T cells formed a stable
immunological synapse and promoted
CD62LhiCD25+Foxp3regulatory T cell generation . In our reports,
transwell insertion during B-T coculture abrogated Treg-of-B
cell induction suggesting that cell-cell contact between B
and T cells was essential. By applying blocking
antibodies during B-T coculture, both CD80 and CD86
on splenic B cells were required to induce functional
]. In consistent with above, Etemire et al.
demonstrated that addition of anti-CD28 antibody to the
B-T cell co-culture decreased the suppressive activity of
Treg-of-B cells. Lower activity of the PI3K/AKT pathway
was associated with Foxp3- regulatory T cell generation
]. IL-10-deficient Treg-of-B cells and Treg-of-B cells
induced in the presence of anti-IL-10 neutralizing
antibody remained their suppressive function suggesting that
IL-10 was not critical for their induction [
64, 67, 68
results suggest that the interaction between B-T cells is
indispensable for the differentiation of Treg-of-B cells.
Treg-of-B cells differ from well-known Treg cells
To date, several molecules have been identified for their
strong association with Treg-of-B cells that are
conserved in single peptide-induced and anti-CD3/CD28
antibodies-induced methods. Treg-of-B cells expressed
higher levels of LAG3, ICOS, PD1, GITR, OX40
(CD134), and CTLA4 compared to those on naïve CD4
+CD25- T cells (Fig. 1). Another group demonstrated
that antigen-presenting B cells facilitated naïve T cells to
convert into CD4+CD25+CD62L+Foxp3- IL-10-producing
regulatory T cells [
]. Our published and unpublished
data showed that Treg-of-B cells did not express Foxp3,
Helios, or neuropilin-1 [
], and these also confirmed
by using Foxp3-GFP reporter mice . These evidence
differentiates Treg-of-B cells from Foxp3-expressing Treg
cells (Table 1).
Th3 cells are well-known that they exert
TGF-βdependent inhibition and express LAP on surface [
Although Treg-of-B cells produced TGF-β compared
with naïve CD4+CD25- T cells [
], TGF-β did not
play a role in their suppressive mechanism . In our
unpublished data, Treg-of-B cells did not express LAP.
These indicate that Treg-of-B cells are different from
Tr1 cells are characterized by IL-10-mediated
suppression and the higher production of IL-10 [
]. In recent
years, CD49b, LAG3, and CD226 were identified as the
surface markers for human and mouse Tr1 cells [
our results, Treg-of-B cells produced a higher amount of
IL-10 compared with naïve CD4+CD25- T cells [
Repeated stimulation of B cells induced long-term
Tregof-B cells with higher expression of ICOS, CTLA4,
CD49b, and c-Maf, but not CD226. In addition to the
difference in surface marker, IL-10 seems to be
dispensable in the inhibitory mechanism of Treg-of-B cells and
these would be described in the later section. These
observations suggest that this Treg-of-B cell is a new
type of regulatory T cells and different from Tr1 cells.
In addition to regulatory T cells, Treg-of-B cells did
not share characteristics with follicular T helper (TFH)
cells. TFH cells expressed BCL-6, CXCR5, ICOS, PD1,
and c-Maf and CXCR5 conferred TFH cells migration to
B follicles [
]. Although Treg-of-B cells expressed
ICOS, PD1 and c-Maf, they did not express the critical
molecule BCL-6 and CXCR5 (data not shown). These
indicate that Treg-of-B cells could not migrate into
follicle to facilitate B cell as TFH cells did.
Furthermore, Treg-of-B cells were hypoproliferative to
stimulation and did not express T-bet, GATA3, or
] and our unpublished data). Treg-of-B cells
produced higher level of IL-10, TGF-β, and IL-4 and lower
or no IL-2, IFN-γ, IL-17, or tumor necrosis factor
68, 69, 71
]. These data confirm that Treg-of-B
cells have anergic characteristics and are not
proinflammatory T helper cells.
Application of Treg-of-B cells
The therapeutic effects of CD4+Foxp3- Treg-of-B cells
has been described in several murine disease models
(Fig. 2). Adoptive transfer of Treg-of-B cells prevented
mice from graft-versus-host disease in a murine model
of heart transplantation [
]. Peyer’s patch
B-cellinduced ovalbumin (OVA)-specific Treg-of-B cells
protected mice from Th2-cell-mediated airway
hyperresponsiveness (AHR), airway inflammation, and IgE
hyperproduction in allergic asthma in an antigen-specific fashion
]. In addition, splenic B-cell-induced OVA-specific
Tregof-B cells shared several characteristics with oral antigen
administration activated CD4+CD25+ T cells, including
elevated expression levels of ICOS, PD1, and CTLA4 and
enhanced non-antigen-specific suppressive functions [
Monoclonal antibody-induced Treg-of-B cells prevented
mice from osteolysis and joint inflammation in
collageninduced arthritis [
]. Prophylactic transfer of Treg-of-B
cells also protected mice from T-cell-induced Th1- and
Th17-dominant inflammatory bowel disease [
together, naïve B cell without cytokines or chemical
supplements is able to induce functional CD4+Foxp3- regulatory
T cells and that B-cell-induced regulatory T cells is an
economical strategy for cellular therapy for different
T-helpercell-dominant inflammatory diseases.
Treg-of-B cells possess both IL-10-dependent and IL-10independent suppressive functions
IL-10 as an anti-inflammatory cytokine is an issue in
Treg-of-B cells suppressive function. As described above,
IL-10 does not play a crucial role in Treg-of-B cells
differentiation. Chen and Chu et al. reported that LAG3
+Treg-of-B cells produced higher amount of IL-10 and
both IL-10 and LAG3 play the roles in their inhibitory
]. Long-term Treg-of-B cells
increased expression levels of CTLA4 and IL-10, both of
which were involved in their suppressive functions .
IL-10-deficient mice were used to confirm the role of
IL-10 in the regulation; however, IL-10-deficient
Tregof-B cells remained suppressive activities [
seems to be dispensable in the inhibitory mechanism of
Treg-of-B cells. Although IL-10 plays a more important
role in long-term Treg-of-B cells than in short-term
Treg-of-B cells, three-day short-term culture is sufficient
for the generation of Treg-of-B cells. These suggest that
there might be unknown inhibitory factors in Treg-of-B
cells suppressive functions.
Studies have demonstrated that ICOS controls IL-10
production and functional CTLA4 expression in Treg
]. PD1 recruits SHP-1 and SHP-2 to
intrinsically downregulate T cell receptor signaling, which
maintains an anergic phenotype in Treg cells [
Mouse Treg cells constitutively expressed GITR and
OX40 and involved the tTreg cells development as well
as their functions [
]. All regulatory-T-related
molecules on Treg-of-B cells, including IL-10, TGF-β,
LAG3, CTLA4, ICOS, PD1, GITR, and OX40, might
confer partial suppressive activities to compensate for
single blockage or neutralization. The critical molecules
controlling Treg-of-B cell phenotype and regulatory
mechanisms remain priorities for investigation. The
inhibitory functions of Treg-of-B cell depend on the
suppressive molecules on the surface or soluble
mediators that require short distance.
B-cell-induced CD4+Foxp3+ regulatory T cells
Reports have revealed the role of B cells in the
development of Treg cells. Naïve primary B cells preferentially
induced the expansion of allogenic CD4+Foxp3+ T cells
rather than CD4+Foxp3- T cells [
]. Splenic B cells
converted allogenic naïve T cells into Foxp3+ regulatory
T cells in the presence of TGF-β and IL-2, and
peritoneal B cells induce Th17 cells . Human
CD40activated B cells induced the differentiation of CD25
+Foxp3+CD62L+ regulatory T cells more efficiently than
immature DCs [
]. In contrast, reports
demonstrated that murine CD40-activated B cells promoted
CD4+ T cell proliferation and effector functions [
Furthermore, the frequency of intrathymic B cells
correlated with that of tTreg cells, and B cells
colocalized with tTreg cells in the thymus [
Intrathymic B cells expressed autoimmune regulator
(Aire), increased the levels of MHC class II and CD80,
and contributed to T cell negative selection for central T cell
]. Taken together, there are unknown
criteria, such as MHC class II-TCR signaling, the B cell
activation status, and different types of tissue resident B
cells, that may fine-tune the expression of Foxp3 in
B-cellinduced regulatory T cells.
To date, we know that naïve antigen-presenting B cell is
sufficient to induce CD4+Foxp3- regulatory T cells
without additional cytokines or chemicals in an IL-10- and
IL-27-dispensable and cell-cell contact-dependent
manner. The expression levels of characteristic molecules
differentiate Treg-of-B cells from well-known T helper
and regulatory T cells as a brand-new type of CD4
+Foxp3- regulatory T cells (Fig. 1). Treg-of-B cells
possess IL-10-depedent, IL-10-independent, and cell-cell
contact-dependent suppressive abilities in
antigenspecific and non-antigen specific fashions. Compared to
long-term Treg-of-B cells, short-term Treg-of-B cells act
through multiple suppressive pathways, and thus a
blockade strategy would be more easily overcome
through compensation by other pathways. Treg-of-B
cells exhibit immunomodulatory effects in Th2-, Th1-,
and Th17-medated diseases and even allogeneic
transplantation. Nevertheless, the physiological conditions or
cues necessary for Treg-of-B cell generation remain
unknown. What is the fine-tuning mechanism for B cells
to induce CD4+Foxp3- or expand CD4+Foxp3+ T cells?
What factors determine the kinetics, memory, and
maintenance? And, most importantly, how could we use
Treg-of-B cells in immunotherapy?
Breg: Regulatory B; Foxp3: Forkhead box P3; ICOS: Inducible T-cell co-stimulator;
IL-10: Interleukin 10; iTreg: in vitro-induced Treg; LAG3: Lymphocyte-activation
gene 3; PD1: Programmed cell death protein 1; pTreg: Peripherally derived
regulatory T; TGF-β: Transforming growth factor-β; Th3: Type 3 helper; Tr1: Type
1 regulatory T; Treg: Regulatory T; Treg-of-B: B cell-induced regulatory T;
tTreg: Thymus-derived regulatory T
This study was supported by the grant from Excellent Translational Medicine
Research Projects of National Taiwan University College of Medicine and
National Taiwan University Hospital (104C101-81).
Availability of data and materials
C-H C performed the literature reviewed and drafted the manuscript. B-L C
supervised and critically reviewed the manuscript. Both authors read and
approved the final manuscript.
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