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particular chemokine receptor:ligand pairs have been linked to the ability
of donor Tregs to suppress GVHD in murine transplant models. While the
literature describing these effects is limited, such studies can generally be
divided into two principal categories. The first examines chemokine recep-
tors that are expressed by naïve and central memory T cells and contrib-
ute to the constitutive trafficking of donor T cells into recipient lymphoid
sites, and the second focuses on so-called inflammatory receptors, whose
expression is upregulated after T-cell activation and which play a role in
cellular migration into peripheral GVHD target organs. With respect to the
former, the chemokine receptor that has been most extensively studied is
the CC-chemokine receptor 7 (CCR7). CCR7 is a G-protein-coupled recep-
tor expressed by both naïve Tcons and Tregs and binds to two structurally
unique ligands, CCL19 and CCL21
[29]
. In nontransplanted animals, CCR7
plays a critical role in the trafficking of T cells into lymph nodes and the
splenic white pulp and appears to be absolutely required for normal Treg
function
in vivo
[86]
. The contribution of CCR7 to the immunosuppressive
properties of donor Tregs following HCT has been addressed in two recent
studies. In the work by de Jager et al.
[87]
C57BL/6 (“B6”) recipient mice
were lethally irradiated before receiving HCT from B6 CCR7
−/−
donors. In
this setting, recipient animals went on to develop disease manifestations
that included weight loss, thymic atrophy, hepatic inflammation, and ulti-
mately accelerated mortality. Notably, however, these results were obtained
with the use of
syngeneic
donor/recipient pairs and did not involve the
administration of alloreactive donor Tcons. As a result, this model system
was arguably more relevant to generalized autoimmune disease than to the
more traditional GVHD encountered in the allogeneic transplant setting.
410
In a subsequent work
[30]
, the contribution of CCR7 to donor Treg function
was evaluated in the allogeneic setting by comparing the ability of wild-type
(WT) and CCR7
−/−
B6 Tregs to prevent lethal GVHD when administered
with alloreactive WT B6 Tcons and WT B6 bone marrow cells to haplotype-
matched B6×DBA2 F1 recipient mice. In this study, CCR7
−/−
Tregs were
surprisingly effective in preventing acute GVHD, with 100% of the animals
receiving CCR7
−/−
Tregs surviving to the end of the study period. Additional
studies using CCR7
−/−
Tregs transgenic for enhanced green fluorescent pro-
tein revealed that CCR7
−/−
Tregs demonstrated an early, transient deficiency
in their ability to accumulate within the host spleen, lymph nodes, and Pey-
er's patches after HCT (J. M. Coghill and J. S. Serody, unpublished obser-
vations) so that by transplant day +14 CCR7
−/−
and WT Tregs were present
at similar numbers within host secondary lymphoid tissue. Collectively
these data suggest that in the proinflammatory, lymphopenic environment
that develops after myeloablative conditioning, compensatory, non-CCR7-
dependent pathways allow for residual Treg trafficking into host lymphoid
organs. Furthermore, these results are consistent with a “threshold effect,”
whereby a minimum number of donor Tregs within host lymphoid tissue
mediates protection from GVHD as long as their intrinsic immunosup-
pressive properties remain intact. Notably, the transplant experiments
described above
[30]
utilized WT bone marrow cells, a situation in which
newly derived Tregs arising from the donor bone marrow would possess an
intact CCR7 signaling axis. As a result, one cannot rule out the possibility
that the indefinite absence of CCR7 signaling by donor Tregs might result in
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