Immunology and Cell Biology (2013) 91, 491–492
& 2013 Australasian Society for Immunology Inc. All rights reserved 0818-9641/13
NEWS AND COMMENTARY
Bach2 in control of regulatory T cells
Transcription factor Bach2 balances tolerance
and immunity
Axel Kallies and Ajithkumar Vasanthakumar
Immunology and Cell Biology (2013) 91, 491–492; doi:10.1038/icb.2013.32; published online 2 July 2013
D uring thymic T-cell development,
CD4 þ regulatory T cells that express
the transcription factor Foxp3 (Tregs) differ-
entiate alongside conventional CD4 þ T cells.
While the former restrict the expansion of
autoreactive and inflammatory T cells,1
the latter are precursors for specialized
populations of CD4 þ T helper (Th) cells
that promote immune responses.2 Commit-
ment to a functionally distinct population of
CD4 Th cells is determined by several subset-
specific transcription factors. These factors
have important roles in setting up Th-specific
transcriptional programs and are involved
in the suppression of alternate cell fate
decisions, a common principle of lineage
commitment. This process, although sup-
ported by subset-specific transcription
factor themselves, also utilizes more
widely expressed transcriptional repressors
to aid in the stabilization of the lineage.2
A recent paper in Nature by Roychoudhuri
et al.3 shows that the transcriptional repressor
Bach2 performs such a role by positively
regulating Treg development and repressing
the effector differentiation programs of
conventional CD4 T cells, thereby maintain-
ing the balance between tolerance and
immunity.
Originally considered a B cell-specific
transcription factor, Bach2 deficiency results
in poor germinal center formation and anti-
body class switching.4 A subsequent study on
B cells demonstrated that Bach2 suppresses
expression of the plasma cell-determining
transcription factor Blimp1,5 which con-
sequently leads to elevated plasma cell
A Kallies and A Vasanthakumar are at The Walter and
Eliza Hall Institute of Medical Research, Parkville,
Victoria, Australia and The Department of Medical
Biology, University of Melbourne, Parkville, Victoria,
Australia
E-mail: kallies@wehi.edu.au
www.nature.com/icb
mice.6
numbers in Bach2-knockout
Interestingly, Blimp1 deficiency could rescue
class switching in Bach2-deficient B cells,
indicating that premature plasma cell
differentiation of Bach2-knockout B cells
was responsible for their failure to isotype
switch.6
In their new and exciting study,3 the
authors demonstrate that Bach2-knockout
mice develop a slowly progressing wasting
disease, which they link to the loss of Treg
function and derepression of conventional
effector CD4 T cell differentiation. Using
RNA and ChIP sequencing to assess the
genome-wide functions of Bach2, the
authors reveal that Bach2 represses multiple
genes associated with CD4 effector T-cell
differentiation. Strikingly, Bach2 constrained
full differentiation within multiple Th
effector populations, including Th1, Th2
and Th17 cells, by directly regulating genes
involved in Th polarization and differentia-
tion, such as Irf4, Blimp1, Ahr, Gata3 and
Il12r. Moreover, its absence during Tgfb-
induced iTreg polarization resulted in an
inappropriate diversion to Foxp3  effector
cells, and using gain-of-function experi-
ments, the authors convincingly show
that this loss of Foxp3 þ cells was a
direct consequence of Bach2 deficiency.
Interestingly, Bach2 was also required for
efficient formation of natural Tregs in the
thymus and consequently for the suppression
of inflammation in a manner that was Treg
cell dependent (Figure 1). Bach2-deficient
mice showed a severe reduction of Tregs,
which was exacerbated in a competitive
situation in bone marrow chimeric mice.
Thus, the authors have identified Bach2 a
s a factor of striking importance at
multiple levels for the control of immune
homeostasis.
Although this study demonstrates that
Bach2 broadly stabilizes immunoregulatory
capacity and represses the differentiation
programs of multiple effector lineages in
CD4 þ T cells, it also reveals that we are still
far from fully understanding how Tregs arise
in the thymus and which factors maintain
their integrity and function in the periphery.
In fact, although several different mechan-
isms have been identified, it is still unclear
precisely how Tregs execute their regulatory
function in vivo. In the context of this study,
although Foxp3 induction in vitro and Treg
numbers in vivo were diminished in the
absence of Bach2, stability of Foxp3 in
existing Tregs was not affected. Bach2-knock-
out Tregs were able to suppress T-cell pro-
liferation similar to their wild-type
counterparts, and they expressed similar or
even higher levels of molecules considered
critical for immune regulation, such as
CD25, CTLA-4 and GITR. However, despite
these features, Bach2-deficient Tregs could
not suppress colitis induced by adoptive
transfer of naı̈ve T cells into a lymphopenic
host, demonstrating that Bach2 has a role in
Tregs beyond its requirement for develop-
ment (Figure 1). One clue may come from
the finding that Bach2 regulates the expres-
sion of chemokine receptors such as
CCR4 and CCR9. Mounting evidence sug-
gests that Tregs can further differentiate into
specialized subsets in the periphery in
response to diverse inflammatory stimuli.
This Treg subset differentiation is dictated
by an array of ancillary transcription factors
that act in conjunction with Foxp3.7–13
One feature of these Treg subsets is
their ability to migrate to distinct tissue
locations. Impaired or deregulated
expression of chemokine receptors or
ancillary transcription factors leads to
incorrect tissue localization and localized
inflammation. Thus, it is feasible that Bach2
controls peripheral differentiation and
function of Tregs at multiple levels.

492
Bach2
IL-2
FoxP3
Bach2
CD4
Bach2
Thymus
Periphery
Figure 1 Regulatory T cell fate and CD4 effector T-cell differentiation are linked by Bach2. Bach2 is
highly expressed in CD4 single-positive thymocytes. Whereas conventional CD4 T cells appear to
develop normally in the absence of Bach2, efficient Treg development in the thymus requires Bach2.
After the activation of naı̈ve CD4 T cells in the periphery, Bach2 restricts the development of multiple
CD4 effector populations and promotes the differentiation of induced Tregs by directly repressing
genes required for Th commitment, such as Irf4, Nfil3, Blimp1, Ahr, Gata3 and Il12r. Tregs
themselves require Bach2 for efficient control of T-cell-mediated immune pathology.
Although the requirement for Bach2 for
Treg differentiation is clearly demonstrated in
the current study, its precise role in this
process awaits further study. Repression of
the effector program during iTreg differentia-
tion is sufficient to explain deficiencies in the
generation of induced Tregs; however, it is
unclear how these would impact on Treg
generation in the thymus, as repression of the
effector differentiation program appears an
unlikely requirement at this early phase of
Treg development. Thus, it is possible
that Bach2 directly has an impact on the
thymic selection of Tregs or the induction of
Foxp3 itself, and it remains a fascinating
subject of further study to illuminate pre-
cisely how Bach2 exerts its function
during Treg development and influences the
function of mature Tregs during immune
regulation.
Immunology and Cell Biology
News and Commentary
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