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how GITR affects GVHD development through Tregs has not yet been
evaluated.
CD30-deficient mice display elevated numbers of thymocytes because of a
gross defect in the negative selection, but have a normal number and phe-
notype of mature T cells in the periphery and lack obvious immunologic
abnormalities [172] . Other studies suggest that CD30 + T cells, present at
sites of inflammation in autoimmune diseases such as rheumatoid arthri-
tis, may serve a regulatory role [173] . The development and homeostasis of
nTregs are not impaired in CD30 −/− mice, and CD30 −/− nTregs have intact
suppressive function in vitro [174] . However, CD30 was found to be criti-
cal for CD4 + CD25 + Tregs to suppress allograft rejection induced by CD8 +
memory cells in vivo. In agreement, Zhang et al. [175] described CD30 as a
unique marker on antigen-induced T cells with regulatory properties that
prevented allograft rejection by inducing the apoptosis of activated T cells.
CD30 can also serve as a marker to distinguish suppressive FOXP3 + Tregs
among nonsuppressive FOXP3 + Teffs after in vitro activation of human
CD4 + T cells [176] . In allogeneic BMT, Zeiser et al. [177] investigated the
role of CD30 signaling in Treg-cell function during acute GVHD. They
found that nTregs derived from CD30 −/− donor mice were significantly less
effective in preventing GVHD lethality. Early blockade of the CD153/CD30
pathway with a neutralizing anti-CD153 mAb reduced Treg expansion and
Treg-mediated protection from proinflammatory cytokine accumulation
and donor T-cell apoptosis. These data demonstrate that early CD30 sig-
naling is critical for Treg-mediated acute GVHD protection after allogeneic
BMT [177] .
213
Another TNFR family member involved in the modulation of Treg suppres-
sion is 4-1BB. Unlike resting CD4 + and CD8 + T cells, Tregs constitutively
express 4-1BB, which can be further increased by TCR or IL-2 stimulation.
Engagement of 4-1BB on Tregs increases their expansion without affecting
their function [178,179] . Interestingly, 4-1BBL −/− mice have a small but sig-
nificant decrease in number of Tregs [89] . However, in a study using a mixed
culture of 4-1BB −/− Teffs and 4-1BB +/+ Tregs, 4-1BB ligation with anti-4-1BB
on the Tregs suppressed their function in vitro without inducing their pro-
liferation. Moreover, delivery of anti-4-1BB and CD25 + 4-1BB +/+ Tregs accel-
erated GVHD mediated by 4-1BB-deficient effectors in vivo [180] . Provision
of 4-1BB ligand abrogates Treg suppression in standard coculture assays,
and this is largely believed to reflect a role for 4-1BB signaling in rendering
Teffs resistant to suppression rather than impairing Treg function [178,181] .
The study of costimulatory molecules on Tregs is in its infancy. It is of
critical importance to target costimulatory molecules that will specifically
inhibit Teffs without inhibiting Treg homeostasis or suppressive function.
An ideal costimulatory target will be the one that specifically augments
Treg number and/or suppressor function without boosting Teff genera-
tion (i.e., unlike CD28 signaling). Although conventional T cells can be
converted to FOXP3 + Tregs in vitro by activation in the presence of TGF-β,
spontaneous conversion in allogeneic BMT in vivo is extremely rare [45] .
Although it has been hoped that costimulatory blockade would promote
this process, in vivo studies have not shown clear-cut evidence that anti-
CD154 or CTLA4-Ig enhances conversion of non-Tregs into FOXP3 + Tregs.
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