Biology Reference
In-Depth Information
to effectively suppress Th1 immune responses
[76]
and likewise IRF-4 and
STAT3 for suppression of Th2 and Th17 responses, respectively
[77,78]
. One
potential explanation for this parallel development of effector and regula-
tory T cell populations would be that expression of these canonical tran-
scription factors (a) endows Treg cells with the same migratory potential as
the respective effector cells, (b) enables them to adapt similarly well to the
polarized environment and thus ensures their survival and proliferation on
site, and (c) activates a specific set of their suppressive machinery that is
most relevant and operates most efficiently in a particular tissue or under a
particular inflammatory condition
[79]
.
Treg in experimental SCT
Since Treg cells were first identified in autoimmune settings and shown to
react strongly and predominantly to “self” antigens, it was unclear in the
beginning whether they would also suppress Tconv cells after allogeneic
stimulation. When cultured with MHC-mismatched stimulatory cells, such
as T-cell-depleted splenocytes or isolated DC, Tconv cells proliferate vig-
orously, with responder frequencies around 0.1-10%, depending on the
degree of MHC discrepancy and the combination of inbred strains. In con-
trast to Tconv cells, Treg cells do not proliferate in such mixed-lymphocyte
reactions. However, when cocultured with Tconv they dose-dependently
suppress their proliferation, comparable to their effect after polyclonal
stimulation
[80,81]
. These initial findings prompted a number of research
groups, including our own, to investigate the suppressive potential of Treg
cells
in vivo
in allogeneic hematopoietic stem cell or organ transplantation.
252
The role of Treg cells in allogeneic bone marrow transplantation (BMT)
was initially examined in experimental murine models of GVHD. In such
models, lethally irradiated (or otherwise preconditioned) recipient mice
are transplanted with a T-cell-depleted donor BM graft for hematopoietic
reconstitution together with peripheral T cells (either unseparated spleno-
cytes or isolated T cells from spleen and/or lymph nodes) for the induction
of GVHD. In initial experiments, depletion of CD25-expressing cells from
splenocytes was sufficient to increase GVHD severity and lethality after
MHC-mismatched BMT and thus provided first evidence that Treg cells
transplanted at physiological ratios (i.e. as constituents of the peripheral T
cell pool) ameliorate the detrimental effects of alloreactive donor CD4
+
as
well as CD8
+
effector T cells in the host
[82,83]
.
Treg cells themselves do not induce any clinical signs of GVHD, even when
transplanted in high numbers and across complete MHC barriers
[81,84]
.
They are, however, not inert, as they have been shown to facilitate engraft-
ment of allogeneic BM cells and thus foster hematopoietic reconstitution
and the establishment of sustained donor chimerism in such situations
[85-87]
. Recent studies by Fujisaki and colleagues
[88]
, demonstrating that
Treg cells reside in close proximity to hematopoietic stem cells (HSC) in the
bone marrow and thereby critically contribute to the generation and main-
tenance of the HSC niche, further support these earlier findings.
As mentioned above, Treg transplanted in a physiological ratio with CD4
+
and CD8
+
Tconv cells only ameliorated GVHD. Yet, follow-up studies in
Search WWH ::
Custom Search