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MHC types, such as B10 (H-2
b
), B10.D2 (H-2
d
) and B10.A (H-2
a
), could
induce GVHD in newly transplanted B10.BR mice, demonstrating that
the filtering required miHA presentation on the MHC shared by the donor
and host in the GVHD pair
[66]
. T cells filtering through P → F1 chimeras
were still capable of causing lethal GVHD in F1 mice, suggesting that for
miHA-disparate GVHD, BM-derived cells were essential for trapping
[67]
.
CD8-mediated GVHD
Despite data in lymph node (LN) filtering experiments, Korngold and Sprent
[67]
found that donor → recipient chimeras, in which host APCs were mostly
replaced by donor APCs, were not resistant to GVHD mediated by donor
CD8 cells. This suggested that host hematopoietic APCs are not required and
that donor APCs are capable of effectively cross-presenting host antigens,
that parenchymal host cells primed donor CD8 cells, or both. Alternatively,
residual host hematopoietic APCs could have been responsible for the
GVHD observed. In support of the last conclusion, B6 β2-microglobulin
−/−
(β2M
−/−
) → WT B6 chimeras were resistant to GVHD when retransplanted
with C3H.SW (H-2
b
) BM and purified CD8 cells
[68]
. Similarly prepared
C3H.SW → B6 chimeras were also resistant to GVHD, indicating that even
when donor-type APCs were long term residents in recipients, they could
not cross-prime donor CD8 cells sufficiently to establish clinical and his-
topathologic GVHD. β2M
−/−
→ B6 chimeras
[69]
and intact β2M
−/−
mice
[70]
were also resistant to induction of CD8-mediated GVL when retransplanted
with C3H.SW BM and CD8 cells, consistent with the GVHD results. There-
fore, at least in this model system, when purified CD8 cells were infused,
presentation by host hematopoietic APCs was essential and cross-presen-
tation by donor APCs or direct presentation by host nonhematopoietic cells
was not sufficient.
180
Using the same C3H.SW → B6 MHC-identical, miHA-mismatched model
in which host APCs were found to be required for GVHD induction, a role
for donor-derived APCs was also found. When C3H.SW β2M
−/−
(MHCI
−
)
donor BM was transplanted along with WT C3H.SW CD8 T cells into
WT B6 recipients, GVHD was still induced, but it was reduced in sever-
ity, particularly in the skin
[32]
. These results suggested that donor APCs
cross-presented host miHAs to donor CD8 cells, but this was not directly
demonstrated.
In subsequent experiments to specifically study cross-presentation in the
same C3H.SW → B6 strain pairing, donor CD8 responses against host-derived
H60 and host-derived chicken ovalbumin (OVA) were studied
[33]
. To do so,
B6 hosts that express H60 or OVA were used as recipients. H60 and OVA both
contain dominant epitopes presented by H-2 K
b
. To enforce presentation
of these K
b
-restricted peptides to cross-presenting donor APCs, H60- and
OVA-expressing B6 mice were crossed to B6 K
b−/−
mice. When these mice
were irradiated and reconstituted with C3H.SW BM and CD8 cells (with
CD4 cells included, as CD8 responses to H60 and OVA are CD4-dependent),
robust CD8 responses against both H60 and OVA were observed, even when
the targeted antigen was restricted to hematopoietic or nonhematopoietic
cells. Cross-presentation per se was not CD4-dependent in that when donor
memory CD8 cells specific for OVA were infused without CD4 help, donor
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