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alloreactive cells from these tissues and their spread to other target organs.
Finally, an alternative explanation for the appearance of priming by non-
hematopoietic cells could be that nonhematopoietic MHC molecules are
transferred to hematopoietic cells
[33,86-89]
.
These studies, by design, examined alloreactive T-cell priming in a situation
wherein antigen presentation by hematopoietic cells was limited. If nonhe-
matopoietic cells are sufficient under these conditions, as the data support,
an important question is what is the relevance of this mode of priming in
the presence of competent hematopoietic APCs? Host and in some cases
donor hematopoietic cells are sufficient for GVHD and GVL induction
[32, 51, 90-92]
and therefore the role of nonhematopoietic cells as APCs is
difficult to study when hematopoietic cells are intact. An intriguing area
wherein nonhematopoietic stimulation of donor T cells could be an impor-
tant mechanism would be in the setting of MHC-mismatched transplants.
If host hematopoietic cells were solely responsible for continued stimu-
lation of T cells that recognize mismatched MHC, one might predict that
such cells would become ignorant of antigen over time as host hematopoi-
etic APCs are eliminated. It is possible that some of these fully alloreactive
cells are propagated by host epithelial cells.
183
Specific hematopoietic APC subtypes in GVHD
Dendritic cells
Among APCs, dendritic cells have been suggested to be the most efficacious in
priming naïve T cells
[93]
, which are potent inducers of GVHD
[94]
. DCs were
therefore thought likely to be the primary host APC responsible for priming
donor alloreactive T cells. Multiple subsets of DCs have been described
[8,
93, 95]
, based on their residence in SLTs or in nonlymphoid tissues; their pre-
cise locations within these tissues; specific cell surface marker expression,
including the expression of receptors important for binding pathogens
[22]
;
and various specialized functions, such as the ability to cross-present exog-
enous antigen
[96-100]
. Despite widespread antigen, tissue-resident DCs
from different organs could theoretically indirectly present tissue-restricted
minor histocompatibility antigens or may imprint T cells with homing prop-
erties specific to tissues such as skin or intestine
[101-103]
. Aside from their
roles after migration to LNs, tissue DCs could modify immune responses
in
situ
by further activating or even suppressing infiltrating alloreactive T cells
initially primed in secondary lymphoid tissues.
The role of host DCs in stimulating the alloresponse during the initiation
of GVHD has been examined in depth, and the results have been surpris-
ing. Zhang et al.
[104]
reported that host DCs upregulate CD86 and MHCII
and concentrate in T-cell zones in the spleen early post-radiation. Nearly
all host DCs were eliminated within 5 days after total body irradiation (TBI)
and coincident with this, naïve allogeneic donor T cells transferred at day
5 proliferated less than those transferred within the first 24 h, arguing that
host DCs are required to initiate the alloresponse.
Duffner et al.
[91]
used an “add-back” approach to demonstrate that host
CD11c
+
DCs isolated from spleen are sufficient to induce donor T cells
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