Biology Reference
In-Depth Information
receptor:ligand interactions contribute to T-cell activation by alloantigens
during the development of GVHD
[33]
. CCL3 may also have a direct effect
on T-cell differentiation; addition of CCL3 to antigen or anti-T-cell recep-
tor (TCR)-stimulated T cells
in vitro
results in the generation of IFN-γ-
producing cells via a mechanism that is independent of IFN-γ or IL-12
[13]
.
Consistent with this finding, polyclonal activation of T cells from CCL3-
deficient mice produce 50% less IFN-γ compared to wild-type controls
[13]
.
CCL2 is known to modulate T-cell polarization. Specifically CCL2 has been
shown to contribute to the development of Th2 responses and may do so
by decreasing IL-12 and enhancing IL-4 production
[13]
. Administration of
CCL2 during CD4
+
T-cell activation either via antigen-pulsed APCs or TCR
cross-linking leads to increased IL-4, but not IFN-γ, secretion. Moreover,
mice deficient in CCL2 have diminished T-cell responses, are functionally
Th2 deficient, and are resistant to lethal infection by
Leishmania major.
In
addition, Kim and co-workers found that CCL2 could serve as a potent acti-
vator of CD8
+
cytolytic T-lymphocyte (CTL) activity, a finding that was asso-
ciated with the increased expression of IFN-γ and TNF-α (reviewed in
[18]
).
Chemokines can also directly regulate activation and function of other
immune cell types (i.e., NK cells, monocytes, neutrophils) that are opera-
tive during the effector phase of GVHD. Chemokines including CCL2, CCL3,
CCL5, and CXCL10 can increase NK cell activity
[34]
and CXCL8 is known
to enhance neutrophil degranulation
[18]
. Although not classically consid-
ered part of the chemokine family, antimicrobial peptides known as defen-
sins not only have chemotactic activity, but, via interactions with Toll-like
receptors, can enhance DC maturation and function and thereby directly
affect T-cell-mediated immune responses
[35]
. Recently, the reduced pro-
duction of α-defensins by Paneth cells targeted during inflammation in the
GI tract in recipient mice with GVHD was found to be responsible for a shift
in the gut flora from commensals toward
Escherichia coli,
a phenomenon
that mechanistically linked the previously recognized association between
GVHD and infection following allogeneic HCT
[36]
.
402
Immune cell recruitment to GVHD target organs
OVERVIEW
Leukocyte migration into target tissues during stage 3 of GVHD is orches-
trated within a dynamic milieu of chemotactic signals in which several
chemokine receptors may be triggered simultaneously or consecutively
(reviewed in
[37]
). Chemokines produced by resident epithelial cells and
macrophages present in organs such as the gut, lung, and liver are positively
charged and bind to extracellular matrix and cell surface heparin sulfate
proteoglycans. Locally retained, these chemokines can thereby establish a
concentration gradient around the inflammatory stimulus and on the sur-
face of the overlying endothelium
[16]
. The migrating leukocyte must there-
fore distinguish between a hierarchy of signals within the tissue in order to
successfully reach the site of inflammation. Chemokine receptors are differ-
entially expressed on subsets of activated/effector cells, and upon stimula-
tion, cells can rapidly switch chemokine receptor expression, acquiring new
migratory capacity
[13]
. The remainder of this section focuses on specific
chemokine receptor:ligand interactions and their potential contribution to
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