Regulating Treg Cells at Sites of Inflammation
Christopher A. Lazarski,1Angela Hughson,1Dorothy K. Sojka,1and Deborah J. Fowell1,*
1David H. Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, Department of Microbiology
and Immunology, University of Rochester, Rochester, NY 14642, USA
Regulatory T (Treg) cells are emerging as
common components in the development
of immunity to both self and foreign anti-
gen. With their ubiquitous participation
comes the need to regulate the regulators
to ensure protective immunity proceeds.
Previous studies suggest that the very co-
factors that boost an immune response to
infection, such as Toll-like receptor (TLR)
modulate Treg cell function. Therefore,
defining the key molecular players in the
reciprocal regulation of effector and Treg
cell function at sites of inflammation be-
comes critical to understanding autoim-
mune and infectious pathologies.
In the May 2008 issue of Immunity,
Tang et al. (2008) proposed a model for
the local loss of immune regulation in the
diabetic pancreas of the nonobese dia-
betic (NOD) mouse (Tang et al., 2008).
Treg cells can be demonstrated to have
protective effects on the development of
unclear whether a loss in Treg cell func-
tion is causative in disease progression.
The study revealed a striking difference
in expression of CD25 by Foxp3+Treg
cells in the draining lymph node versus
that by the cells in the pancreas of
diabetic mice. Foxp3+Treg cells in the in-
flamed pancreas expressed markedly
less CD25 than their lymph node counter-
parts. The authors proposed that the
genetic defects in IL-2 production in the
NOD (Yamanouchi et al., 2007) led to
the loss of CD25 expression and thereby
compromised Treg cell survival. In sup-
port of this notion, boosting Treg cell
numbers and their expression of CD25
with low-dose IL-2 treatment prevented
The reduction in CD25 expression by
Treg cells in the diabetic pancreas was
an important observation but prompted
questions as to whether this potential
control mechanism for Treg cells was
a more general consequence of the
inflammatory milieu. With a keen interest
in the regulation of CD4 effector function
at tissue sites of inflammation (Katzman
and Fowell, 2008), we have analyzed the
expression of CD25 by Foxp3+Treg cells
in the dermis of non-NOD mouse strains
after a number of immune challenges in-
cluding Leishmania major and OVA-CFA
(ovalbumin-complete Freund’s adjuvant)
in the dermis and influenza in the lung.
With notable similarity to the NOD pan-
creas, we found that reduced expression
of CD25 by Foxp3+Treg cells was a gen-
eral phenomenon in inflamed tissues of
BALB/c (Figure S1 available online) and
C57BL/6 mice. We conclude that the re-
T cells in the diabetic pancreas is neither
autoimmune nor NOD specific. Nonethe-
less, it will be important to determine
whether reduced IL-2 production, the
mechanism proposed for the CD25 mod-
ulation by the authors, is common to
these other inflammatory sites.
Our results extend the observations
made by Tang et al. (2008) to highlight
a common Treg cell phenotype at sites
of inflammation. Further dissection of the
components that are within the inflamma-
tory milieu and that regulate CD25 ex-
pression is required, and confirmation
that the loss of CD25 compromises Treg
note, the ability of human CD4+T cells to
transiently upregulate Foxp3 without the
acquisition of regulatory function raises
the possibility that the CD25loFoxp3+
cells we find accumulating at sites of
CD25hiFoxp3+Treg cells. Establishing
the lineagerelationship of theCD25locells
to the CD25hicells will be critical. Thus,
the fate of Foxp3+Treg cells on entry
into inflamed sites remains unclear but
well worth pursuing.
Supplemental Data include one figure and can be
This work was supported by grants from the
National Institutes of Health and the Juvenile
Diabetes Research Foundation.
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Immunity 29, October 17, 2008 ª2008 Elsevier Inc.