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GVHD, and in particular on APC function. In contrast to the MHC-mismatched
situation, miHAs presented by MHCs shared between the host and the donor
can be presented by either host or donor APCs, as is detailed below. MiHAs
can also have variable tissue distributions, and this could affect the types of
APCs and the locations of APCs on which miHAs are initially presented to T
cells. Finally, it is worth pointing out that the lower precursor frequency of T
cells reactive against miHAs could affect which types of APCs can function-
ally initiate anti-miHA responses. That is, less effective APCs may be able to
activate MHC-mismatched T cells, but not miHA-reactive cells.
Direct versus indirect presentation of miHAs and
cross-priming
Direct antigen presentation is the presentation of a peptide antigen on
MHCI or MHCII when that peptide is derived from a protein synthesized by
the same cell. Although direct presentation is conventionally thought to be
the province of epitope generation on MHCI, there is also direct presenta-
tion of endogenous peptides on MHCII
[42]
. Indirect presentation refers to
the presentation of peptide antigens on MHCI or MHCII molecules when
the peptides are derived from proteins acquired from exogenous sources
and via multiple pathways, including endocytosis and pinocytosis of
free-floating proteins and antibody-bound proteins, Fc-receptor-mediated
ingestion, and uptake of apoptotic and necrotic cells
[43-45]
. The pro-
cessing of exogenously acquired antigens to generate epitopes on MHCI
is called “cross-presentation,” whereas the activation of T cells against
cross-presented antigens is called “cross-priming”
[46,47]
. Cross-priming is
restricted to a smaller subset of APCs relative to those cells that can indi-
rectly present antigens on MHCII. This restriction is probably due to limited
expression of the subcellular machinery needed to generate these epitopes.
This seems to limit cross-presentation and cross-priming to a subset of
lymphoid-tissue residents, including CD8αα
+
DEC-205
+
DCs, and certain
tissue-resident, migratory DC subsets, including those that express CD103
[46,48,49]
. Cross-presentation and cross-priming are further regulated
by signals indicative of an activated immune system, including Toll-like
receptor (TLR) ligands, CD40L, and type 1 interferons (IFNs)
[33]
.
176
The specifics of indirect presentation are of interest in allo-BMT (
Figure 9.1
)
because host hematopoiesis, which includes host APCs, is eliminated within
the first 1-2 weeks
[50-52]
, because of the combination of pretransplant con-
ditioning and killing by donor T and NK cells. Continued miHA presentation
by donor hematopoietic APCs therefore requires processing of host antigens
and indirect presentation by donor-derived APCs. It is for this reason that
indirect presentation in GVHD has been subject to investigation
[32,53]
.
The roles of host-derived hematopoietic and
nonhematopoietic APCs in GVHD
MHC-mismatched models
That host APCs could have a role in GVHD initiation was suggested by
the ease with which donor T cells initiate GVHD in MHC-mismatched
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