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ISSN: 1538-4101 (Print) 1551-4005 (Online) Journal homepage: http://www.tandfonline.com/loi/kccy20

Gfi1: A unique controller of Treg cells

Lewis Zhichang Shi & Hongbo Chi
To cite this article: Lewis Zhichang Shi & Hongbo Chi (2013) Gfi1: A unique controller of Treg
cells, Cell Cycle, 12:23, 3581-3582, DOI: 10.4161/cc.26824
To link to this article: http://dx.doi.org/10.4161/cc.26824

Copyright 2013 Landes Bioscience

Published online: 21 Oct 2013.

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Editorials: Cell Cycle Features

Editorials: Cell Cycle Features

Cell Cycle 12:23, 35813582; December 1, 2013; 2013 Landes Bioscience

Gfi1

A unique controller of Treg cells

Lewis Zhichang Shi and Hongbo Chi*
Department of Immunology; St. Jude Childrens Research Hospital; Memphis, TN USA

Regulatory T cells (Treg), defined by

the expression of the transcription factor Foxp3, are crucial for immunological
self-tolerance and homeostasis.1 Treg cells
are mainly developed in the thymus as
natural Treg cells (nTreg), which can be best
depicted by a 2-step model. The initial signals from the high-affinity T-cell receptor
(TCR) and CD28 co-stimulation lead
to the generation of a precursor population with enhanced cytokine responsiveness, which then responds to signals from
c-dependent cytokines, especially IL-2
for full induction of Foxp3 expression.2
Consistent with the importance of
TCR and co-stimulatory signals for nTreg
development, several transcription factors downstream of TCR/CD28 have
been implicated in Foxp3 expression2. For
instance, among TCR-activated NFB
members, c-Rel has a crucial role in Foxp3
induction by binding to an intronic conserved noncoding sequence (CNS) in the
Foxp3 locus, known as Foxp3-CNS3.2
Concurrent with transcriptional activation of Foxp3 expression, TCR stimulation also leads to epigenetic modification
by establishing a Treg -specific CpG hypomethylation pattern in Foxp3-CNS2, as
well as in other Treg signature genes.3 Both
transcriptional activation of Foxp3 expression and establishment of Treg -specific
epigenetic modifications are required
for a full developmental and suppressive
program of nTreg cells. Aside from TCR/
CD28 stimulation, IL-2 directly contributes to Foxp3 transcription by activating
Stat5, and thus is intimately linked to
nTreg development.2 IL-2 is also required
for functional programming and expansion of nTreg cells during thymic development.4 While remarkable advances have

been made in deciphering TCR- and IL-2induced intrinsic events in nTreg development, how the production of extrinsic
signals such as IL-2 is controlled remains
poorly understood.
We addressed this issue by focusing on
growth factor independent 1 (Gfi1), a transcription repressor important for immune
and hematopoietic cell development and
function. Since Gfi1 has been implicated
in early thymocyte development,5 we utilized a mouse genetic model with T cellspecific deletion of Gfi1 via CD4-Cre
(Gfi1CD4-Cre) to circumvent the early developmental defects associated with germ-line
deletion of Gfi1. We identified a previously unappreciated mechanism in which
Gfi1 exerts a non-cell-autonomous effect
to curtail nTreg development by inhibiting IL-2 production from conventional T
cells6 (Fig.1). Combining pharmacological blockade of IL-2 signaling and genetic
deletion of Il2, we showed that excessive
IL-2 production in Gfi1CD4-Cre mice underlined the augmented nTreg development
in Gfi1CD4-Cre mice. Furthermore, when
wild-type bystander cells were introduced
into a Gfi1CD4-Cre-predominant environment created by bone marrow chimeras,
they exhibited an increased proportion
of Foxp3 + nTreg cells, indicative of an
nTreg -inducing environment established
by Gfi1-deficient thymocytes. This noncell-autonomous effect of Gfi1 on nTreg
development was further supported by
the lack of effect on nTreg development
when Gfi1 was deleted selectively in Treg
cells. Importantly, the increased generation of nTreg cells in the absence of Gfi1
was independent of its pro-survival effect.
Taken together, Gfi1-mediated transcriptional control of extrinsic signals

(IL-2) orchestrates an unconventional

mechanism for nTreg development, thereby
complementing the well-recognized Treg intrinsic transcriptional pathways.
Deficiency of Gfi1 not only led to
increased generation of nTreg cells, but
also potentiated their suppressive activity.6 Because tumor-infiltrating Treg cells
have a crucial role in dampening antitumor immunity, we examined whether the
increased Treg cellularity and function in
the absence of Gfi1 impaired antitumor
immunity. When challenged with B16
melanoma cells, Gfi1CD4-cre mice were
unable to control late-stage tumor growth,
associated with significantly elevated Treg /
non-Treg ratios. Moreover, Gfi1-deficient
nTreg cells showed increased expression of
Treg effector molecules CD103 and CD73
under steady-state and in the tumor environment. The integrin molecule CD103
marks the subset of Treg cells with elevated
suppressive activity in various contexts,
including antitumor responses, whereas
the ectonucleotidase CD73 is important for converting the proinflammatory
extracellular ATP to immunosuppressive
adenosine. Therefore, Gfi1 deficiency in
T cells established a tumor-supportive
environment by both increasing Treg cellularity in tumors and endowing them
with a greater suppressive activity via
upregulating CD103 and CD73 expression. Mechanistically, direct inhibition
of CD103 and CD73 by Gfi1 has been
reported in induced Treg cells7 and TH17
cells,8 respectively. Our results support
and extend these findings by showing that
Gfi1-deficient nTreg cells express elevated
levels of CD103 and CD73.6 It is also
noteworthy that the effect of Gfi1 deficiency on CD103 upregulation appeared

*Correspondence to: Hongbo Chi; Email: hongbo.chi@stjude.org

Submitted: 08/28/2013; Accepted: 09/05/2013
http://dx.doi.org/10.4161/cc.26824
Comment on: Shi LZ, et al. Proc Natl Acad Sci U S A 2013; 110:E3198-205; PMID:23918371; http://dx.doi.org/10.1073/pnas.1300950110

www.landesbioscience.com

Cell Cycle 3581

nTreg -suppressive activity by mitigating IL-2 production from conventional

T cells and by directly regulating nTreg
effector molecules, respectively. Given
the extensive effects of Gfi1 deficiency on
nTreg development and function, strategies
to enhance Gfi1 expression and/or activity represent a possible approach for antitumor immunotherapy.
References

Figure1. Control of Foxp3+ nTreg cells and antitumor immunity by Gfi1. Loss of Gfi1 in conventional
T cells (Tconv) leads to increased secretion of IL-2, which promotes nTreg cell expansion in the thymus
and periphery. Gfi1 deletion also upregulates Treg effector molecules CD103 and CD73. Collectively,
Gfi1 deficiency in T cells dampens antitumor immunity. , increased expression or cellularity.

to be less pronounced in the absence of

IL-2 (our unpublished findings), suggesting that enhanced IL-2 production in the
unmanipulated Gfi1CD4-cre thymus also
contributes to CD103 upregulation. This
interpretation is consistent with the effect
of IL-2 to upregulate CD103 and CD73
expression for functional maturation of
thymic nTreg cells.4 We therefore propose
that Gfi1 deficiency upregulates CD103

3582

and CD73 expression in nTreg cells via both

direct and indirect mechanisms, thereby
potentiating nTreg -mediated immunosuppression in Gfi1CD4-Cre mice.
In conclusion, Gfi1 orchestrates an
important cell-extrinsic control mechanism for nTreg development by regulating IL-2 production from conventional
T cells. Further, Gfi1 likely exerts
both extrinsic and intrinsic effects on

Cell Cycle

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