Biology Reference
In-Depth Information
CD70/CD27 pathway
CD70 and CD27 have similar expression patterns in mice and humans.
CD27, a member of the TNFR family, is constitutively expressed on thymo-
cytes, naïve T cells, B cells, and NK cells. Upon T-cell activation, the expres-
sion of CD27 is upregulated and then downregulated after several rounds
of division and differentiation toward effector cells. Its ligand, CD70, is a
type II transmembrane glycoprotein belonging to the TNF family. CD70 is
expressed on APCs and is rapidly induced on both T and B cells upon cellu-
lar activation
[103]
. Antigen stimulation on T and B cells and Toll-like recep-
tor triggering on B cells and DCs induce CD70 expression, which is further
enhanced by CD40 triggering
[104,105]
. Although CD27 is expressed on thy-
mocytes and naïve T cells, CD27 seems not to play a critical role in T-cell
generation and maintenance, as CD27-deficient mice have normal num-
bers of T cells in the thymus as well as peripheral lymphoid organs. How-
ever, more detailed analyses on CD27
−/−
mice revealed that CD27 deficiency
has a more profound impact on CD8
+
, rather than CD4
+
, T cells
[106]
. CD27
is not required for entry into the cell cycle upon T-cell activation or for the
differentiation toward IFN-γ-producing or cytolytic effector T cells. Instead,
CD27 promotes survival of activated T cells throughout successive rounds
of division and thereby contributes to the accumulation of effector T cells
[107]
. It has also been found that CD27 on CD8
+
T cells can induce prolif-
eration in the absence of IL-2, which does not lead to T-cell differentiation
[108]
. These studies indicate that CD27 triggering alone is neither required
nor sufficient to induce effector cell formation, but that CD27 contributes to
the accumulation of effector T cells by inducing proliferation and survival.
Further studies showed that CD27 expressed on CD4
+
T cells promotes both
the primary CD8
+
T-cell response and the secondary expansion of memory
CD8
+
T cells, and thus CD27 instructs CD4
+
T cells to provide help to CD8
+
T
cells through Th1 cytokines such as IL-2 and IFN-γ
[109]
.
207
The role of CD27 in the alloimmune response has been studied in a mouse
cardiac transplant model. Blockade of CD70/CD27 interaction prolonged
allograft survival in WT recipients and induced long-term graft survival
in the absence of CD28 costimulation. CD70 blockade had little effect on
CD4
+
-mediated allograft rejection, but prevented CD8
+
-mediated rejec-
tion by inhibiting proliferation and effector function of CD8
+
T cells and
reducing CD8
+
memory T cells
in vivo
[110]
. Thus, the CD27/CD70 pathway
appears to be critical for CD8
+
T-cell activation, especially in the absence of
CD28/B7 costimulation. In a clinical study, expression of CD27 on periph-
eral CD4
+
T cells correlated with the development of severe acute GVHD
after allogeneic HCT
[111]
. However, the direct involvement of the CD70/
CD27 pathway in the development of GVHD remains to be determined.
HVEM/LIGHT pathway
HVEM is a member of the TNFR family and acts as both ligand and recep-
tor. As a ligand, HVEM engages members of the Ig superfamily, BTLA and
CD160 (discussed above). As a receptor, HVEM binds the canonical TNF-
related ligands lymphotoxin-α (LTα) and LIGHT, both of which are TNF
family members. LTα is expressed on stromal cells and macrophages, but
does not provide a costimulatory signal. In contrast, LIGHT is expressed on
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