Antigen presentation and antigen-presenting cells in graft-versus-host disease - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 172

different APCs have distinct functions in different infections is well beyond
the scope of this review; however, broadly this relates to access to antigens,
the presence of subcellular machinery for cross-presentation, the PAMPRs
expressed, and the signaling events downstream of pathogen- or stress-
derived signals.

Using this paradigm of APC function in T-cell responses to pathogens as a
framework, we can highlight some clear differences between anti-pathogen
responses and GVHD. First, every residual host APC can directly present
alloantigen, and every donor-derived APC has access to host miHAs in the
surrounding host tissues. This is akin to every host APC (and for that mat-
ter every host cell) being infected with a virus and presenting virus-derived
peptides. In contrast, in pathogen- or allergen-directed responses, access
to antigens in part dictates which APCs prime T cells. A consequence of
this difference is that in allogeneic hematopoietic stem cell transplantation
(allo-BMT) a wider array of cells, especially host hematopoietic cells, can
stimulate alloreactive T cells. Second, APC maturation and migration to sec-
ondary lymphoid organs are no longer linked to a specific pathogen. Rather,
in alloimmune responses, APCs stimulated to mature for any reason might
become effective APCs for promoting GVHD. These maturation signals
may not be pathogen products, but may come in the form of intracellular
products such as ATP [30] , complement [31] , or other as yet unknown cel-
lular “danger signals” generated secondary to ongoing malignancy, chronic
infection or pretransplant conditioning. And, unlike responses to infection,
by which antigens are largely eliminated, in GVHD alloantigens, particu-
larly antigens expressed by nonhematopoietic/parenchymal tissues, are
essentially limitless. While GVHD may promote elimination of host hema-
topoiesis, APCs derived from the donor bone marrow graft will continue to
be able to acquire and present host antigens [32,33] .

175

Major versus minor histocompatibility antigens

The presence or absence of MHC mismatches has significant implications
for the roles of host and donor APCs in alloimmune T-cell responses. With
an MHC mismatch, some donor alloreactive T cells will recognize (and be
restricted by) the mismatched host MHC. In the solid-organ transplanta-
tion parlance this has been called “direct allorecognition.” In the setting
of an MHC mismatch between donor and recipient, the precursor fre-
quency of alloreactive donor T cells has been estimated to be quite high,
between 1 and 10%. Various theories have been proposed to explain the
high precursor frequency of T cells that can recognize an MHC mismatch
[1, 34-39] . However, a discussion of this is beyond the scope of this chapter.
Importantly, donor T cells directed against mismatched MHC should not
be able to interact with donor APCs, unless those APCs acquire intact host
MHC molecules.

In MHC-identical allo-BMT, donor T cells distinguish nonself (host) from
self (donor) via TCR-mediated recognition of miHAs, which are MHC-bound
peptides derived from proteins encoded by polymorphic genes present in
the host but not in the donor [40,41] . The targeting of miHAs as opposed to
an MHC mismatch + peptide has broad implications for the pathobiology of