Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 110

populations activated through both direct and indirect antigen presenta-
tion pathways could facilitate marrow engraftment, and the recipients
showed durable tolerance to donor skin and cardiac allografts [151] . Tregs
activated singularly through direct antigen presentation did not facilitate
engraftment, but the study did not formally demonstrate indirect antigen
presentation, for example by pulsing B6 APC with DBA/2 antigens or dem-
onstrating T-cell specificity for indirectly presented peptide epitopes [151] .

Within the context of marrow transplantation, recipient Tregs that survive
the conditioning regimen expand rapidly in the lymphoid compartment
[153,154] . Recipient Tregs can be expanded in situ after sublethal TBI in vivo
by administering rmIL-2 complexed to an anti-IL2 mAb [152,155] . The
expansion and activation of these recipient CD4 + CD25 + FoxP3 + Treg cells
correlated inversely with the numbers of immunodominant anti-donor
MiHA (H60)-specific CD8 T cells in MHC-matched allogeneic recipients.
These results demonstrated that the expanded recipient Treg populations
prevented the development of anti-donor antigen-specific CD8 T cells in
the recipient [152] .

Other investigators reported that recipient Treg expansion after reduced
intensity conditioning facilitated engraftment of male marrow cells in syn-
geneic female recipients [153] . Recipient Tregs persisting after transplan-
tation can regulate NK-dependent resistance, since depletion of Tregs by
treatment with CD25-specific antibody augmented resistance mediated by
NK cells [150] . Since TCR engagement and appropriate signaling are neces-
sary for Treg activation and function, studies are needed to understand the
contribution of allogeneic and self-antigens in the stimulation of specific
populations of recipient and donor Treg cells post-transplant.

112

Since murine Treg cells cannot interact directly with CD8 and CD4 T cells,
APC are a likely mechanism for Treg-induced suppression of these cells
[156,157] . The results from studies employing recipient Tregs to block resis-
tance could be explained by Treg engagement of class II + donor APC and
regulation at this interface. Thus, it can be postulated that in transplants
containing recipient anti-donor specific Tregs, these cells will engage donor
APCs where they can promote engraftment by suppressing host-versus-graft
responses. In contrast, the concomitant addition of “third-party” grafts will
contain APC not engaged by the anti-donor specific Tregs, and therefore this
interface will remain “free” to activate specific resistance responses result-
ing in the survival of only the donor hematopoietic graft [151,157] . Consis-
tent with such a hypothesis are findings suggesting that recipient anti-donor
responses may be elicited primarily by direct interaction with donor APC.
If so, donor APCs could serve as a site where Tregs and conventional T-cell
effectors that recognize donor alloantigens could intimately interact [134] .

Tregs can produce cytokines that regulate hematopoiesis, including TGF-β
and IL-9 [158,159] . Activated Tregs suppressed certain hematopoietic pro-
genitor populations in vitro and in vivo after co-transplantation with mar-
row in lethally irradiated syngeneic recipients [145] . Since Treg cells have
been identified within the marrow stem cell niche, and since their presence
is associated with engraftment in an MHC-mismatched transplant model,
Treg cells within the marrow might also have a role in the regulation of
engraftment [19] .