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C3H.SW APCs were capable of stimulating them. Therefore the genera-
tion of peptide:MHCI itself does not absolutely require CD4 help, whereas
effective priming may be CD4-dependent. Cross-priming was even demon-
strated in the fully MHC-mismatched B6 → BALB/c model by using BALB/c
hosts transgenic for OVA. This cross-priming was found to require donor
DCs that express both CD40 and the type 1 IFN receptor, identifying these
pathways as targets for treating GVHD and for augmenting cross-priming
for GVL.
CD4-mediated GVHD
Relative to cross-presentation of antigens on MHCI, indirect presentation on
MHCII is more efficient, can be performed by a broader subset of cells, and
is less tightly regulated. Based on this difference in processing, one might
predict that donor-derived APCs would be sufficient for CD4-mediated
GVHD, and in mouse models this indeed has proven to be the case. Jones
et al.
[61]
generated B6 → BALB/c chimeras and then retransplanted these
mice with B6 BM and CD4 cells and found that GVHD was readily induced,
indicating that long-term donor-type APCs are sufficient to initiate GVHD.
Similarly B6.C (H-2
d
) → BALB/c chimeras, when retransplanted with B6.C
BM and CD4 cells, also developed GVHD similar to that of control BALB/c →
BALB/c chimeras, with the exception of less skin disease
[71]
. To better
isolate the effects of initial CD4 priming, to donor or host APCs, experi-
ments were performed with CD80/CD86
−/−
B6.C donors and CD80/CD86
−/−
BALB/c recipients. GVHD was completely prevented when BM donors and
hosts were CD80/86
−/−
, demonstrating that GVHD initiation was CD80/
CD86-dependent. This is consistent with the dominance of naïve CD4 cells
in this and other models
[72-74]
. When only hosts or donors were CD80/
CD86
−/−
, similar GVHD developed relative to wild-type controls, with the
exception of less skin or less bowel GVHD, respectively. These data dem-
onstrated that while host or donor APCs were sufficient, donor and host
APCs had nonoverlapping roles in GVHD initiation. Despite these data,
CD4-mediated GVL in MHC-matched, miHA-mismatched models required
intact host APCs
[69,70]
. This difference may reflect that host APCs that sur-
vive conditioning initiate donor T-cell priming earlier than do donor APCs,
which must first engraft, and that this early priming is necessary for survival
in these GVL models.
181
Where does T-cell priming occur?
Classical paradigms of T cell activation posit that naïve T cells are primarily
activated in lymph nodes and spleen. Some of this dependence has been
hypothesized to be due to the efficiency with which rare antigen-reactive
T cells
[75,76]
can be brought into proximity of competent antigen-bearing
APCs
[77,78]
. However, in the allo-BMT setting, antigen is ubiquitous and
the precursor frequency of alloreactive T cells is high, so it was reasonable to
propose that GVHD could be induced in the absence of LN and spleen. To test
the location of T-cell priming in GVHD, several groups examined GVHD in
hosts that genetically lack lymph nodes, with or without splenectomy. Over-
all, GVHD was reduced but not completely eliminated in splenectomized
alymphoid (aly/aly)-
[79,80]
and lymphotoxin-α (LTα)-
[81]
deficient mice,
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