Antigen presentation and antigen-presenting cells in graft-versus-host disease - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 182

suppressive effect of pretransplant Flt3-ligand, as host Tregs can suppress
GVHD [113] . A role for host APCs in activating the suppressive functions
of allogeneic donor Tregs during GVHD has also been demonstrated [114] .

DC ablation approaches have also been taken to analyze the roles of donor
DCs; this work is described in more detail in prior sections. Donor DCs were
shown to be key for cross-priming CD8 + T cells against host miHAs and to
play a major role in indirectly priming donor CD4 cells [33,53] .

Langerhans cells

Langerhans cells (LCs) are a distinct subset of tissue DCs restricted to
the epidermis [99] , in part characterized by the expression of the C-type
lectin receptor langerin [115] . Mice also express langerin in a subset of
nonepidermal DCs, including dermal DCs, which can be distinguished
from epidermal LCs by the expression of CD103 on the latter and EpCam
on the former [116] . It had long been hypothesized that LCs are essential
for adaptive immune responses against antigens in the skin, including con-
tact hypersensitivity and skin graft rejection [117] . Contrary to this view, we
and others used mice deficient in LCs to show that LCs are not required
for contact hypersensitivity reactions and skin graft rejection [118-121] ,
and unexpectedly some contact-hypersensitivity and skin-graft-rejection
responses were augmented in the absence of LCs [119,120] . However, more
detailed analyses of LCs in cutaneous immune responses have revealed
stimulatory functions that do not overlap with other cutaneous DC subsets
[4,121-124] . LCs have long been of interest in allo-BMT because the skin is
the most commonly affected and most easily accessible site of GVHD. In
human allo-BMT, LCs can remain recipient in origin even after the rest of
the hematopoietic system has largely converted from being host derived to
being donor derived [125,126] .

185

Merad et al. studied LC turnover and recruitment to the skin after allo-BMT
[127] and their role in GVHD response in an MHC-mismatched model [85] .
Host LCs were shown to persist in the epidermis after lethal irradiation and
T-cell-depleted allo-BMT [127] , whereas the inclusion of allogeneic T cells
induced the elimination of recipient LCs, facilitating the engraftment of
donor LCs [85] . Fully allogeneic donor → host chimeras developed GVHD
when retransplanted with donor BM and T cells; however, the elimination
of host LCs by either a small dose of T cells in the initial transplant or UVC
treatment diminished skin GVHD.

In contrast to the ability of allogeneic T cells to induce the turnover of LCs
in an MHC-matched model, in two MHC-matched, miHA-mismatched
models, donor T cells did not completely eliminate host LCs [128,129] . Also,
in a CD8-dependent MHC-matched, miHA-mismatched model, residual
host LCs in donor → host chimeric recipients were not sufficient to induce
GVHD [68,129] . These data suggest that the sufficiency of LCs to induce
GVHD is model dependent and may depend on the strength of the alloim-
mune response.

While the aforementioned BM chimera experiments addressed whether
LCs are sufficient, they did not determine whether LCs are required for
GVHD when other APC subsets are available. This issue was addressed