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activated T cells, NK cells, and also immature dendritic cells and provides
a costimulatory signal on T cells independent of the CD28 pathway [112] .
Costimulation mediated by LIGHT enhances T-cell proliferation and Th1-
cytokine secretion [113] . In addition to its effects on T cells, LIGHT contrib-
utes to dendritic cell maturation, enhanced by CD40L, resulting in further
T-cell activation [114] .
As a costimulatory molecule, LIGHT has been found to play an important
role in alloreactivity and GVHD. Blockade of LIGHT by its soluble receptors
inhibits the induction of DC-mediated primary allogeneic T-cell response
in vitro. Engagement of LIGHT costimulates human T-cell proliferation,
amplifies the NF-κB signaling pathway, and preferentially induces the pro-
duction of IFN-γ but not IL-4 [113] . Using LIGHT- or HVEM-deficient (KO) T
cells, in vivo studies showed that anti-host CTL activity of donor T cells was
completely abrogated, and survival of the recipient mice was significantly
prolonged. In the absence of LIGHT-HVEM costimulation, alloreactive
donor T cells undergo vigorous apoptosis while their proliferative poten-
tial remains intact. Furthermore, blockade of LIGHT with a soluble receptor
was able to reduce GVHD and improve survival in preclinical mouse BMT
models [115] . However, this protective effect was detected only in CD8- and
not in CD4-mediated GVHD. The investigators further tested the blockade
of LIGHT combined with CD40L blockade in a murine GVHD model [116]
and found that coblockade starting at the day of BMT completely prevented
acute GVHD and improved survival. However, given that alloantigen-
specific T cells were rendered tolerant, the GVL effect was also impaired.
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GITR/GITRL pathway
GITR, glucocorticoid-induced TNF receptor family-related gene, was
originally identified by a differential display strategy as a gene induced by
stimulation of the TCR in the presence of the glucocorticoid dexametha-
sone [117] . GITR is predominantly expressed on activated Teffs, B cells, NK
cells, and macrophages [117] . One exception is FOXP3 + Tregs, which con-
stitutively express GITR [118] . Its ligand, GITRL, is widely expressed in the
immune system and can be detected at basal levels on APCs such as DCs,
B cells, monocytes, and macrophages, with higher expression following
cellular activation particularly on plasmacytoid DCs. GITRL is also expressed
on endothelial cells as well as on activated T cells. Engagement of GITR on T
cells enhances both CD4 + and CD8 + T-cell proliferation to suboptimal TCR
stimulation and augments the production of cytokines [119] . GITR low-
ers the threshold of CD28 costimulation in CD8 + T cells and is required for
NF-κB activation and Bcl-xL upregulation downstream of CD28 [120] . One
interesting feature of GITR is that its cytoplasmic tail can also activate sig-
naling pathways that trigger apoptotic cell death, suggesting that manipu-
lating the GITR/GITRL pathway could be applied in tumor immunotherapy
and in autoimmune diseases [121] .
The role of the GITR/GITRL pathway in GVHD has not been extensively
studied. Using an MHC-disparate murine BMT model, Muriglan et al.
[122] showed that GITR stimulation in vitro and in vivo enhances allore-
active CD8 + T-cell proliferation, whereas it decreases alloreactive CD4 + T
cell proliferation by increasing apoptosis through the Fas/FasL pathway.
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