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
Background
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
Main text
CD4+Foxp3+ regulatory T cells
Sakaguchi et al. demonstrated that CD4+CD25+ T cells
contributed to maintaining self-tolerance in a
nonantigen-specific manner [
1
]. 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
mouse [
2–4
]. 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 [
5
].
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 [
6
]. tTreg cells could be activated in an
antigenspecific fashion and exerted suppressive activity in a
non-antigen-specific fashion [
7
]. tTreg cells produced
many inhibitory cytokines, including TGF-β1, IL-10, and
IL-35, to downregulate immune responses [
8
].
Furthermore, tTreg cells exhibited cell-cell contact-dependent
suppression via latency-associated peptide (LAP) [
9
],
CD39 (ectonucleoside triphosphate
diphosphohydrolase1, ENTPD1) and CD73 (ecto-5′-nucleotidase) [
10
], and
cytosolic cyclic adenosine monophosphate (cAMP) [
11
].
Reports showed that tTreg cells induced effector T cell
apoptosis via various pathways, including deprivation of
IL-2 and IL-7 [
12
], disruption of effector cell membrane
integrity by granzyme B [
13
], galectin-1-induced
apoptosis [
14
], and the engagement of TNF-related
apoptosis inducing ligand (TRAIL)-death receptor 5
(DR5) [
15
]. Additionally, tTreg cells inhibited effector
T cell activation via downregulation of costimulatory
molecules on DCs through CTLA4 [
16
] and LAG3
[
17
]. These studies indicate that tTreg cells are a
polyclonal population, and the above mentioned
complicated mechanisms result in maximal
immunosuppression during homeostasis.
(...truncated)