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from GVHD
[101,102]
. The impaired function of CD62L
−
iTreg cells
in vivo
correlated with impaired LN homing, reduced
in vivo
proliferation and sur-
vival, and consequently less profound suppression of coadministered Tconv
cells. Thus Treg, like Tconv cells, are best primed and activated in second-
ary lymphoid organs, most likely by the same APC
[103]
. Since it has been
shown that Treg not only drive APC toward a tolerogenic state but also out-
compete Tconv cells in forming long-lasting aggregates with APC
[104,105]
,
this might represent a very efficient way to inhibit activation and prolifera-
tion of alloreactive donor Tconv cells and subsequently their egress and
migration to peripheral tissues in relevant numbers. Yet, it has been shown
that Treg cells deficient in the chemokine receptor CCR5 are less capable of
migrating to the respective tissues (here, liver and lung) and consequently
less effective in ameliorating GVHD in the affected organs
[106]
. Likewise,
forced expression of CXCR3 in Treg cells improved their therapeutic efficacy
in GVHD
[107]
. In summary, these studies support the notion that suppres-
sion occurs not only in lymphoid structures during the priming phase but
also directly in the GVHD target organs in ongoing disease.
Using
in vivo
bioluminescence imaging (BLI) to monitor T cell migration
in allogeneic recipients, Nguyen and colleagues showed that donor Treg,
like GVHD-inducing donor Tconv cells, first home to spleen and LN before
they migrate to peripheral tissues
[90]
. Migration of both T cell popula-
tions seemed to happen simultaneously and correlated with substantially
reduced Tconv cell numbers in the target organs. The gastrointestinal (GI)
tract represents one major target organ of GVHD. In the steady state in non-
transplanted mice, Treg in the GI tract are critically involved in restricting
immune responses to commensal bacteria and food antigens while at the
same time permitting adequate reactions to pathogenic intruders, a process
referred to as mucosal tolerance
[108]
. Establishment of mucosal tolerance
in the gut is based on antigen presentation by classic DC that sample intes-
tinal antigens in the lamina propria before they migrate to MLN where they
prime naïve T cells
[109]
. Unlike in other LN, a large proportion of T cells
in MLN upregulate Foxp3 during their activation, most probably because
of the presence of a subset of CD103
+
DC that is particularly capable of
expressing IDO as well as producing the vitamin A metabolite retinoic acid
(RA). Together with TGF-β, RA is known to support the generation of iTreg
from naïve CD4
+
T cells both
in vitro
and
in vivo
[110]
. In addition, several
commensal bacteria (e.g. certain
Clostridium
species) have been shown to
specifically increase the frequency of iTreg cells in the gut
[111]
. Together
with studies by Lathrop and colleagues
[112]
that revealed substantial dif-
ferences between the TCR repertoires of colonic and thymic Treg cells, these
data indicate that the Treg pool in the gut and in gut-associated lymphoid
structures comprises a significant proportion of locally induced iTreg cells.
This finely balanced equilibrium is severely disturbed after allogeneic
hematopoietic SCT, first by patient conditioning, but then most profoundly
by the development of GVHD. Breakdown of the barrier function of the
mucosa allows entry of pathogenic bacteria and thus induces severe inflam-
mation. This might result in reprogramming of the local DC population and
consequently in its preferential support of proinflammatory effector T cell
differentiation instead of Treg generation, as observed in colitis
[113]
. Based
on a hypothesis recently presented by Barbara Fazekas de St. Groth
[114]
254
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