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transferred these cells to lethally irradiated allogeneic HSCT recipients and
found that they significantly enhance thymic cellularity and chimerism, as
well as peripheral T- and NK-cell reconstitution. Enhanced thymopoiesis was
durable beyond the period of engraftment which is suggestive of a positive
crosstalk between the T-cell precursors and the thymic stroma. T-cell precur-
sors gave rise to host-tolerant mature T cells with normal receptor repertoires,
cytokine secretion and proliferative responses to antigen. T-cell precursors
increased protection against Listeria monocytogenes and mediated signifi-
cant graft-versus-tumor (GVT) activity without GVHD. The progeny of adop-
tively transferred unmodified T-cell precursors was detected up to 6 months
post transfer (Zakrzewski et al, unpublished). Next, we assessed whether
adoptive therapy with T-cell precursors could be performed across MHC bar-
riers as an off-the-shelf therapy. We found that
ex vivo
generated allogeneic
MHC-disparate T-cell precursors engraft in the thymus upon transfer into
irradiated recipients and enhance thymopoiesis and peripheral T- and NK-
cell reconstitution
[149]
. Precursor-derived mature T cells are tolerant to both
host and donor, yet capable of mounting an immune response to third-party
antigens as determined by mixed lymphocyte reaction (MLR) and mediate
potent GVT activity without GVHD. In additional experiments, we demon-
strated that T-cell precursors can engraft in older recipients with involuted
thymi. The damage to the thymic stroma induced by the conditioning regi-
men could be a limiting factor for the efficacy of T-cell precursors. We were
able to demonstrate synergistic effects by combining pre-treatment with KGF
and adoptive transfer of T-cell precursors. Finally, T-cell precursors can be
genetically modifed to enhance anti-tumor activity. These preclinical studies
demonstrate the feasibility of adoptive therapy with allogeneic T-cell precur-
sors across MHC barriers in irradiated recipients
[148,149]
. Future clinical
trials using this approach are being planned.
132
Interleukin-22
Interleukin-22 (IL-22) is an IL-10 family cytokine primarily associated with
maintenance of barrier function and induction of innate antimicrobials at
mucosal surfaces
[150]
. IL-22R is a heterodimer of IL-10Rβ and a specific
IL-22Rα subunit
[150]
. Expression is restricted to non-hematopoietic cells,
primarily of epithelial lineage, thus far identified in skin, pancreas, intestine,
liver, lung and kidney
[151,152]
. The main sources of IL-22 are Th17 cells
and innate lymphoid cell (ILC) subsets, including RORγ (t)
+
lymphoid-tissue
inducer cells (LTi) and NKp46
+
cells
[153-157]
. IL-23 produced by dendritic
cells (DCs) has been implicated in the regulation of IL-22 production by
ILCs
in vivo
[155,158,159]
and is used as a standard strategy for inducing
IL-22 production
in vitro
.
We have recently found that, along with its role in maintaining mucosal bar-
rier function, IL-22 is also a crucial mediator of endogenous thymic regen-
eration after thymic injury
[160]
. This study identified a unique molecular
network of thymic regeneration, triggered by loss of thymic cellularity (and
in particular the depletion of CD4
+
CD8
+
double positive, DP, thymocytes).
Following thymic damage, upregulation of IL-23 by dendritic cells (DCs)
induces the production of IL-22 by innate lymphoid cells (ILCs). IL-22 acts
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