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which Treg and Tconv cells were cotransplanted in a nonphysiological high
ratio of 1:1 clearly demonstrated the ability of Treg cells to protect recipi-
ent mice from GVHD development, even when an otherwise lethal dose of
Tconv cells was administered
[80,82,83]
. Inhibition of GVHD was observed
with both freshly isolated
[80]
and
in vitro
-expanded
[82,83]
donor Treg, but
not by host-derived Treg cells
[80]
. Furthermore, GVHD prevention could
be demonstrated not only in completely MHC-mismatched allogeneic BMT
models
[80,82]
, but also in haploidentical settings (mostly parent into F1
mouse inbred strain combinations
[83]
) and even in miHA-mismatched
situations
[89]
, and ranged from reduced weight loss and increased survival
time to full protection. The use of polyclonal Treg cells proved to be suf-
ficient to inhibit GVHD
[80,84]
, although priming and expansion of Treg
cells by coculture with recipient-derived hematopoietic cells seemed to
improve the protective efficiency on a per-cell basis
[82,83]
. As it has been
shown
in vitro
as well as
in vivo
that Treg cells gain suppressive activity only
after their own activation via their TCR, preactivation during coculture may
accelerate the ability of Treg cells to suppress early events in GVHD devel-
opment in addition to the improvement achieved by preselection of an allo-
antigen-specific TCR repertoire. An alternative strategy to the preactivation
of donor Treg cells
in vitro
prior to transfer is their preactivation
in vivo.
The
cotransplantation of Treg and BM cells 24-48 h before Tconv cell infusion
permitted a reduction in Treg cell numbers and frequencies to almost phys-
iological levels, suggesting that preactivation and expansion
in vivo
under
lymphopenic conditions significantly enhance their efficiency with regard
to GVHD prevention
[90]
.
253
Since the cotransfer of comparably low numbers of Treg cells is sufficient to
protect recipients from GVHD, the question arose as to where and how Treg
cells suppress GVHD-inducing Tconv cells. There is ample evidence for sup-
pression both in secondary lymphoid organs, the priming sites for alloreactive
Tconv cells, and “onsite” in GVHD target tissues where fully activated Tconv
cells are present during the effector phase of GVHD. Host hematopoietic
APC, especially DC, have been shown in multiple studies to be both neces-
sary and sufficient for GVHD induction
[91,92]
. In contrast, antigen presen-
tation by donor-derived or nonprofessional host APC seems less relevant
[93,94]
. Although host APC can be found in almost every tissue, they most
efficiently activate and prime alloreactive donor-derived Tconv cells in the
specialized microenvironment of secondary lymphoid organs. However,
whether lymphoid structures, and especially those associated with GVHD
target organs such as mesenteric lymph nodes (MLN), Peyer's patches, and
cryptopatches, are absolutely required for GVHD induction or simply facili-
tate and accelerate the priming process is still controversial and seems to
depend on the model system
[95-97]
. Nevertheless, transferring Tconv cells
that lack lymph node (LN) homing receptors such as CD62L and/or the
α4β7 integrin results in delayed and less severe GVHD
[98,99]
.
Treg cells also show heterogeneous expression of a number of differ-
ent migratory receptors, including CD62L.
In vitro,
both subpopulations
(CD62L
+
and CD62L
−
) show similar expression of Foxp3, no secretion of
IL-2, and equal suppressive activity after polyclonal or alloantigen-specific
stimulation
[100,101]
. After transfer into MHC-mismatched recipients,
however, only the CD62L
+
subpopulation was able to convey protection
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