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Furthermore, treatment with agonistic anti-GITR mAb increased GVHD
mediated by CD8
+
T cells but decreased GVHD mediated by CD4
+
T cells,
indicating that GITR has opposite effects on the regulation of alloreactive
CD4 versus CD8 T cells
[122]
. A separate group showed that treatment with
a single dose of agonistic anti-GITR mAb converted chronic GVHD to acute
GVHD by activating donor CD8
+
T cells that otherwise would become aner-
gic
[123]
. Given that GITR signaling regulates both Teffs and Tregs, the effect
of GITR on GVHD development through both populations of T cells war-
rants further research.
Regulation of GVHD by costimulation through tregs
While many types of T cells with regulatory function have been described
before, CD4
+
CD25
+
FOXP3
+
Tregs are extensively studied and the best defined,
in large part because they are a distinct T-cell subset naturally developed in
thymus and play a key role in maintaining peripheral tolerance and protect-
ing from autoimmunity in the immune system
[124]
. In addition to main-
taining self-tolerance, Tregs also play an indispensable role in the induction
and maintenance of allograft tolerance
[125]
. In BMT, freshly isolated or
ex vivo
-expanded donor CD4
+
CD25
+
cells present in the marrow inoculum
significantly delay or prevent GVHD in multiple donor-recipient strain com-
binations, although with a low efficiency
[126-129]
. While controlling GVHD,
recipient-specific Tregs have also been shown to favor immune reconstitu-
tion
[130]
. Furthermore, freshly isolated Tregs could control GVHD but still
permit GVT activity against leukemic cells, presumably by preserving the
perforin-mediated killing pathway
[131]
. We and others have demonstrated
that
ex vivo
FOXP3-transduced, antigen-specific Tregs effectively prevent
GVHD
[132]
. In addition to the wealth of data from experimental models,
several groups have shown that a counterpart of mouse CD4
+
CD25
+
cells,
in terms of phenotype and activity
in vitro,
is present in human peripheral
blood
[133-135]
. Expression of FOXP3 in CD4 T cells correlates with their
ability to function as Tregs. CD4
+
CD25
+
T cells, generated as a consequence
of stimulation of CD4
+
CD25
-
human T cells, also express FOXP3 and acquire
Treg function
[136]
. Furthermore, expression of FOXP3 is negatively corre-
lated with the severity of GVHD in the patient
[137]
, indicating that increas-
ing FOXP3 expression and presumably increasing numbers of Tregs over
time were associated with the absence of GVHD, while the absence of FOXP3
expression and presumably low numbers of Tregs were associated with per-
sistence of GVHD. Taken together, these observations suggest that Tregs play
a significant role in the control of GVHD development.
209
Studies of the contributions of costimulatory pathways were originally
focused on Teffs. However, it has become clear that costimulation is also
critical for the development, maintenance, and function of Tregs
[138]
. Sig-
nificant differences in the biology of Teffs and Tregs are reflected by differ-
ences in the roles played by some of the costimulatory molecules on these
two cell types. The initial study showing that CD28 deficiency resulted in
aggressive autoimmunity in the nonobese diabetic (NOD) mouse due to a
defect in Tregs opened up a new field of costimulatory biology on Tregs.
Many costimulatory receptors or ligands that were previously defined as
positive regulators for Teffs, such as CD28, ICOS, OX40, CD40L, and 4-1BBB,
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