Biology Reference
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effect depends on the strength of TCR stimulation, CD28 costimulation, or
IL-2 signaling
[54]
. Furthermore, mice deficient for PD-1 display an auto-
immune phenotype with lupus-like glomerulonephritis and progressive
arthritis
[55]
, indicating that PD-1 negatively regulates immune responses.
However, in comparison with CTLA4
−/−
mice, the autoimmune phenotype
observed in PD-1
−/−
mice is delayed and limited in certain strains of mice
[56]
. More recent studies showed that PD-L1 also binds B7-1, delivering an
inhibitory signal
[53]
.
In MHC-mismatched murine BMT models, T cells deficient for PD-1 had
enhanced ability to cause acute GVHD, and PD-1 blockade with anti-PD-1
mAbs or soluble PD-L1.Fc fusion protein resulted in accelerated GVHD and
enhanced mortality in an IFN-γ-dependent manner
[57]
. While blocking
PD-L1 did not affect
in vivo
proliferation of CD4
+
or CD8
+
T cells regard-
less of CD28 costimulation, blocking PD-L2 resulted in a marked increase
in CD8 response
in vivo.
The effect of PD-L2 on CD8
+
T-cell proliferation is
regulated by CD28 costimulation and by CD4
+
T cells
[58]
. PD-L1 expressed
on recipient parenchymal cells limits expansion of infiltrated T cells and
thus protects the target organ from persistent injury
[59]
. However, PD-1
engagement on donor T cells also constrains GVL effects
[60]
. In fact, PD-L1
blockade can effectively restore the GVL effects mediated by T cells specific
for leukemia-associated antigen
[61]
. Thus, the PD-1/PD-L pathway plays
an important role in the regulation of GVHD and GVL effect. While agonistic
mAbs to PD-1 may represent a novel strategy for preventing GVHD, block-
ade of PD-1 may be applied to promoting the GVL effect mediated by T cells
that do not recognize recipient alloantigens.
202
HVEM/BTLA pathway
B- and T-lymphocyte attenuator (BTLA) is a member of the CD28 family
expressed on activated T cells, B cells, and APCs
[62]
. Herpesvirus entry
mediator (HVEM), the primary ligand for BTLA, is a TNFR family mem-
ber and expressed on activated T, B, and NK cells
[62]
.
This is an example
of costimulatory interaction between Ig and TNFR superfamily members.
Engagement of BTLA by HVEM delivers an inhibitory signal that suppresses
T-cell activation and differentiation
in vitro.
The inhibitory role of BTLA was
evidenced in mice genetically deficient for BTLA, which exhibit amplified
immune responses
in vivo
[63]
. CD160 is another receptor that binds HVEM,
and HVEM/CD160 interaction also delivers a negative signal to inhibit
T-cell activation
[64]
. CD160 is a glycosylphosphatidylinositol-anchored
molecule of the Ig superfamily and primarily expressed on CD8
+
T cells. A
subset of resting CD4
+
T cells also expresses CD160, which is unregulated
upon activation but in turn limits T-cell proliferation
[64]
. Thus, HVEM can
trigger a negative regulation outcome by engaging BTLA or CD160.
In allogeneic BMT models, sustained GVHD could not be induced if BTLA
were blocked using either BTLA-deficient T cells or administration of an
antagonistic anti-BTLA Ab in a nonirradiated parental-into-F1 model
because of impaired survival of donor T cells
[65]
. Using a myeloablative
haplotype BMT model, the same group later showed that BTLA deficiency
in donor or host had no significant effect on GVHD, suggesting that BTLA
does not normally regulate GVHD
[66]
. However, a single administration
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