Biology Reference
In-Depth Information
suitable markers to reliably distinguish thymus-derived from peripherally
induced Treg cells (here referred to as Treg and iTreg, respectively). Shevach
and co-workers proposed Helios, a member of the Ikaros transcription fac-
tor family, which they showed to be expressed only in Treg and not in iTreg
cells in mice as well as humans
[36]
. However, other groups have challenged
these findings
[37,38]
. In a more general approach, the group of Mathis and
Benoist identified a Treg-specific transcriptional signature and showed that
this comprised Foxp3-dependent as well as coregulated, Foxp3-indepen-
dent gene clusters
[39]
. In follow-up studies they compared the transcrip-
tome of Treg with those of various forms of
in vivo
-converted iTreg and
found substantial differences between those cell types, but interestingly no
complete overlap between any of the iTreg and Treg cells
[40]
. Similarly, no
substantial differences were detected in naïve, lymphocyte-replete animals
when the TCR repertoires of thymic Treg cells were compared with those
from spleen and lymph nodes
[41]
. Additional epigenetic studies, performed
in both mice and humans, revealed significant differences between Treg and
iTreg with regard to DNA methylation as well as other epigenetic marks in
the
Foxp3
locus
[11,42-44]
. In particular CpG motifs in the so-called Treg-
specific demethylation region (TSDR), one of three conserved noncoding
sequences within the gene locus that show gene-enhancing/stabilizing
properties, have been shown to be completely demethylated in Treg but fully
methylated in iTreg as well as Tconv cells
[11,45-47]
. Quantitative analysis
of the methylation status of the TSDR is now already used to determine the
proportion of natural Treg cells in patient samples
[48]
. Several transcrip-
tion factors, including CREB/ATF and STAT5 as well as Ets-1, are recruited
to the TSDR and thereby stabilize Foxp3 expression
[11,45,49]
. Most strik-
ingly, however, Foxp3 itself, in a complex with Runx1 and CBFβ, also binds
to this region, thereby actively contributing to the heritable maintenance of
its own expression
[11]
and in consequence most likely Treg cell function.
Thus it could be shown that upon loss of Foxp3 expression, Treg cells lose
many if not all of their specific characteristics, start to secrete proinflam-
matory cytokines, and—most importantly—lose their suppressive activity
[50,51]
. To what degree Treg cells show such plasticity
in vivo
under physi-
ological as well as pathological conditions is still subject to debate. Thus,
several groups showed that Treg cells start to develop into harmful effector
T cells of various types under the influence of inflammatory cytokines such
as IL-6 and IL-1
[52-54]
, whereas others provided evidence for a remarkable
stability of Treg cells even under highly inflammatory conditions
[55]
. In
an attempt to reconcile these discrepant results, Hori and colleagues
[56]
,
by using genetic fate mapping, recently identified a small subpopulation of
CD4
+
Tconv cells that only transiently upregulates Foxp3 and thus, at least
in part, could be responsible for the emergence of so-called “ex-Treg” cells,
i.e. cells that downregulate Foxp3 expression in certain situations, such
as transfer into lymphopenic hosts. Interestingly, transient upregulation
of FOXP3 in nonregulatory T cells upon activation has also been observed
in humans
[57]
and thus adds to the difficulties related to Treg identifica-
tion and isolation (see below). In summary, these studies indicate that the
overall contribution of iTreg (and FOXP3
+
non-Treg) cells to the periph-
eral Treg cell pool might be limited, at least under steady-state conditions
and in lymphoid organs. The situation, however, might be very different in
nonlymphoid tissues and in particular during inflammation. In a model of
249
Search WWH ::
Custom Search