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immunosuppressive metabolites that further hamper Tconv activation and
survival
[68]
.
In 2004 Shevach and colleagues
[69]
showed that Treg cells not only depend
on IL-2 for their maintenance and survival but also require IL-2 produced
by activated Tresp cells in cocultures for fully efficient suppression. At the
same time, they inhibit IL-2 mRNA induction in Tconv cells and thereby
restrain their proliferation
[69]
. Treg cells express all three components of
the high-affinity IL-2 receptor. However, whether excessive IL-2 consump-
tion by Treg cells leads to significant IL-2 deprivation-induced apoptosis in
Tconv cells and whether this represents a major suppressive mechanism of
Treg cells
in vitro
or
in vivo
remains a matter of debate
[70,71]
.
Abrogation of suppression, as observed after physical separation of Treg and
Tconv cells, does not completely exclude the involvement of soluble media-
tors if they have only short-range activity and thus require close proximity
between Treg and the respective target cell to be effective. One such medi-
ator could be cAMP, which has been shown by Bopp and colleagues to be
delivered from Treg to Tconv cells via gap junctions
[72]
. Increased cAMP lev-
els in Tconv cells then result in inhibition of proliferation and IL-2 produc-
tion. Similarly, pericellular production of adenosine from ATP by concerted
action of the ectoenzymes CD39/ectonucleoside triphosphate diphospho-
hydrolase-1 and CD73/ecto-5′-nucleotidase on Treg cells seems to contrib-
ute to their suppressive effect. Adenosine binds to A2A receptors expressed
on activated Tconv cells and then potently inhibits their proliferation
[73]
.
251
Treg cells are constitutively present in secondary lymphoid organs, where
they interact mainly with CD4
+
and CD8
+
Tconv cells and APC. This interac-
tion results primarily in suppression of Tconv cell priming and prolifera-
tion but also inhibits their egress from the lymphoid tissues
[74]
and thus
restrains immune responses already during the induction phase. However,
Treg cells have also been found in nonlymphoid tissues, even under steady-
state conditions, and they are increasingly recruited to these sites during
inflammation, where they are responsible for limiting ongoing immune
responses and thus preventing tissue damage and organ destruction. Effi-
cient recruitment of Treg cells to sites of inflammation is ensured by their
expression of a wide range of chemokine receptors and cell adhesion mol-
ecules that allow them to migrate in response to ligands expressed or che-
moattractants secreted particularly during acute inflammation. Thus, in a
model of concanavalin-A-induced hepatitis, for example, the local release of
IFN-γ leads to upregulation of the CXC-chemokine ligands CXCL9, CXCL10,
and CXCL11 and subsequently to the recruitment of Treg cells expressing
the respective receptor, CXCR3, to the liver
[75]
.
Treg cells have been reported to target—either directly or indirectly—a num-
ber of other cell types apart from T cells and APC, including NK and NKT
cells or osteoblasts, mast cells and B cells
[70]
. In view of the wide variety of
suppressive mechanisms applied by Treg cells, it is easily conceivable that
suppression of, for example, potentially autoreactive Tconv cells in periph-
eral lymph nodes differs substantially from that of fully activated effector
T cells in inflamed tissues. However, whether and how Treg cells “choose”
the most effective mechanism in a given situation is still largely unknown.
Interestingly, it has been shown that Treg cells have to express T-bet
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