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as the cause of immunodysregulation, polyendocrinopathy, enteropathy,
X-linked syndrome, a life-threatening autoimmune syndrome with similar
manifestations in young boys
[6-8]
.
As demonstrated by the above-mentioned thymectomy experiments,
murine Treg cells do not leave the thymus before day 3 after birth. This sug-
gests that Treg differentiation in the thymus is somewhat delayed compared
to Tconv cells. In wild-type mice, a population of CD25
+
Foxp3
−
CD4 single-
positive thymocytes can be detected prior to the emergence of Foxp3
+
Treg
cells
[9]
. These cells show an increased tendency to develop into Foxp3
+
Treg
cells after intrathymic injection and are thus likely to represent Treg precur-
sors
[10]
. Initial induction of Foxp3 seems to take place already in double-
positive thymocytes and critically relies on activation of the NF-κB signaling
pathway downstream of T cell receptor (TCR) engagement. This results in
translocation of the transcription factor cREL to the nucleus and bind-
ing to CNS3, one of three conserved noncoding regions within the
Foxp3
locus with proven enhancer activity
[11]
. In addition, TCR engagement also
results in binding of nuclear factor of activated T cells and activator pro-
tein 1 to the
Foxp3
promoter, thereby further supporting Foxp3 expression.
Costimulation via CD28 seems another important step, as CD28-deficient
mice display a significant reduction in thymic Treg cells
[12]
. Initially, it was
suggested that CD28 signaling is required to enhance the strength of the
TCR signal and thereby contributes to the recruitment of thymocytes into
the Treg pool. However, there is now accumulating evidence that B7/CD28
interactions are dispensable for the lineage decision but that they support
the proliferation of CD25
+
Foxp3
−
Treg precursors and improve their survival
[13]
. IL-2 is critically important for Treg cell homeostasis and function in the
periphery (see below). Similarly, it was shown that binding of IL-2 to CD25
on Foxp3
−
Treg precursors is sufficient to induce upregulation of Foxp3,
most likely via binding of STAT5 to the
Foxp3
promoter and even without
continuation of the TCR signal. Unlike in the periphery, however, IL-2 is not
absolutely required for Foxp3 expression in the thymus, as in its absence
this step can also be mediated by other cytokines signaling through com-
mon γ-chain receptors, such as IL-15
[14-16]
. TCR specificity as well as the
strength and quality of the TCR-major histocompatibility complex (MHC)/
antigen interaction influences recruitment of immature thymocytes into
the Treg cell pool. Initial experiments by Jordan et al.
[17]
in TCR trans-
genic mice demonstrated that Treg cell development occurred only when
the cognate antigen was expressed in the thymus, thus providing the first
hint that TCR specificity—and most likely recognition of “self”—is impor-
tant for Treg cell differentiation. Data describing the TCR repertoire of Treg
cells are highly controversial and provide support for both largely overlap-
ping
[18]
and largely nonoverlapping repertoires of CD4
+
Treg and Tconv
cells
[19-21]
. Yet, recent experiments by Moran et al.
[22]
revealed that the
potential of a thymocyte to differentiate into a Foxp3
+
Treg cell correlates
with the strength of the TCR signal it receives through interaction with anti-
gen/MHC II complexes on antigen-presenting cells (APC), thus supporting
the earlier notion that increased TCR reactivity to self favors Treg cell devel-
opment over that of Tconv cells. Cortical and medullary thymic epithelial
cells (cTEC and mTEC, respectively), together with bone-marrow-derived
dendritic cells (DC), ensure proper antigen/MHC complex presentation to
247
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