Circulation Research. 2000;86:1190-1192
(Circulation Research. 2000;86:1190.)
© 2000 American Heart Association, Inc.
Lymphocyte Trafficking Mediated by Vascular Adhesion Protein-1
Implications for Immune Targeting and Cardiovascular Disease
J. Steven Alexander,
D. Neil Granger
From the Department of Molecular and Cellular Physiology, Louisiana State
University Health Sciences Center, Shreveport, La.
Correspondence to J. Steven Alexander, PhD, Department of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932. E-mail jalexa{at}lsumc.edu
Key Words: lymphocytes cardiovascular disease vascular adhesion protein-1
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Introduction
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The trafficking, extravasation, and retention of
lymphocytes
within certain tissues (eg, lymph nodes) seem to be
mediated
by several classes of specialized adhesion
glycoproteins that
are expressed on the surface of unique
endothelial cells (high
endothelial
venules [HEVs]) that exist in both the blood and
lymph
microvessels.
1 2 The binding of these
endothelial cell
adhesion molecules to their
corresponding ligands on lymphocytes
(L-selectin,
4ß
7,
4ß
1, leukocyte
functionassociated
antigen-1 [LFA-1], and CLA-1) tightly controls
the kinetics
and magnitude of lymphocyte margination, rolling,
adhesion,
and extravasation, thereby allowing these leukocytes to
fulfill
their immune surveillance functions and, in some tissues,
mature
into fully differentiated cells. During inflammation, the
recruitment
and retention of lymphocytes in affected tissues occur at
an
accelerated rate, because locally released mediators (eg,
cytokines,
chemokines, and oxidants) increase the expression of
relevant
adhesion molecules on both the endothelial
cells and leukocytes.
Although much progress has been made in our understanding of the
molecular determinants of lymphocyteendothelial cell
adhesion in the blood circulation, the identification and
characterization of the glycoproteins that mediate this
cell-cell adhesive interaction has tended to lag behind equivalent
efforts made for neutrophilendothelial cell
adhesion.3 4 5 Nonetheless, the efforts to discover and
characterize adhesive determinants on both leukocyte populations have
led to the revelation that lymphocytes and neutrophils share several
glycoproteins, including
ß2-integrins (CD11/CD18), and L-selectin. As a
consequence of these observations, the initial models that were
proposed to explain the coordinated recruitment of leukocytes to sites
of inflammation assumed that neutrophils and lymphocytes followed the
same sequential process and were mediated by a similar complement of
adhesion molecules. With additional experimentation, it was realized
that lymphocytes can use an assortment of unique adhesion molecules
that selectively mediate their rolling and firm adhesion on HEVs.
Furthermore, there is mounting evidence that supports the use of unique
adhesion molecules for the vascular arrest of specific subpopulations
of lymphocytes. An example of such a glycoprotein that
selectively mediates the recruitment of CD8+ T
lymphocytes is vascular adhesion protein-1 (VAP-1).
VAP-1, which was first described by Salmi and Jalkanen in
1992,6 has been proposed as a mediator of the
selectin-independent adhesion of lymphocytes to
endothelial cells in lymph nodes and at sites of
inflammation.6 7 8 9 This endothelial
adhesion molecule is now known to mediate the specific binding of
CD8+ T cells, as well as natural killer (NK)
cells, to peripheral lymph node HEVs independent of
L-selectin, PSGL-1, and
4 integrins. Although VAP-1 does not
function as an autonomous lymphocyte adhesive determinant, it
cooperatively (with LFA-1, Mac-1, and L-selectin ligands) confers
specific binding of CD8+ lymphocytes to lymph
nodes and inflamed endothelia. CD4+ cells do not
bind VAP-1, but use peripheral node addressins for
trafficking.10 Together with peripheral node
addressins, VAP-1 seems to be a major determinant of the flux of
lymphocytes that occurs in some healthy vascular beds (eg, lymphoid
tissue) and inflamed tissue. There is evidence that VAP-1, working in
concert with intercellular adhesion molecule-1, can mediate the binding
of tumor-infiltrating lymphocytes into hepatic carcinomas, suggesting
that VAP-1 may also participate in defense against solid organ
tumors.11
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Structural and Functional Characteristics of VAP-1
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VAP-1 is initially synthesized as a 180-kDa proform, which can
be
cleaved to an 84.6-kDa form with 6 possible N-glycosylation
sites.
12 13 This sialoglycoprotein is
structurally distinct from other
adhesion molecules, especially with
regard to its unusual property
of exhibiting copper-dependent monoamine
oxidase activity.
14 15 VAP-1 also contains an RGD site,
usually assumed to mediate
adhesion to integrin receptors, such as
fibronectin, collagen,
and laminin. Analysis of the VAP-1 gene
reveals that it has
4 exons and 3 introns with multiple transcript
initiation sites,
indicating that there are several possible sites for
modulation
by inflammatory mediators.
16
The active, dimeric form of VAP-1 is restricted to
endothelial cells. A trimeric form has been detected in
smooth muscle cells. However, this molecule does not support lymphocyte
adhesion; instead, it functions solely as an amine
oxidase.17 VAP-1 has been demonstrated within the inflamed
vasculature of skin, gut, liver, pancreas, and
synovium.15 18 19 VAP-1 seems to be shed during some forms
of liver (but not gut or joint) inflammation, which may result in the
downregulation of VAP-1dependent lymphocyte
binding.20
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Lymphocyte Binding to VAP-1
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Although it has been proposed that VAP-1mediated lymphocyte
binding
may be regulated by shedding from the
endothelial cell surface
via differential glycosylation
of the adhesion molecule and
through posttranslational modification,
relatively little is
known about the factors that influence and
regulate this important
controller of lymphocyte trafficking. In this
issue of
Circulation Research, Salmi et
al
21 have significantly extended our understanding
of
the potential role of VAP-1 in sustaining lymphocyte adhesion
under
physiologically relevant conditions of shear
stress, and
they describe a role for CD44 and sialic acid in its
binding
to lymphocytes. Using cultured endothelial
cells transfected
with VAP-1, Salmi et al demonstrated VAP-1dependent
adhesion
of CD8
+ T cells and NK cells under
conditions of physiological
shear stress.
Importantly, VAP-1 mutants lacking either the
RGD or monoamine oxidase
motifs still sustained lymphocyte adhesion.
Salmi et al also
demonstrated that VAP-1 is specific for lymphocytes
and will not
sustain granulocyte binding to the endothelium.
Lymphocyte
binding also required L-selectin, LFA-1, and Mac-1 ligands
but
was critically dependent on VAP-1 expression. Revertants that
lost
the ability to express VAP-1 also lost the ability to bind
lymphocytes.
A novel and significant finding in the study is
that engagement of CD44
on lymphocytes significantly increased
VAP-1dependent adhesion to the
transfected endothelial
cells, suggesting that this
mobilizes the VAP-1 ligand. Additionally,
treatment with sialidase to
remove sialic acid from the lymphocytes
dramatically enhanced
VAP-1dependent lymphocyte adhesion
to the transfected
endothelial cells. These findings raise the
interesting
possibility that CD44 functionally activates a VAP-1
ligand
that enhances and regulates lymphocyte adhesion.
There is a growing body of evidence that implicates T lymphocytes in
the initiation or progression of a variety of
cardiovascular diseases and regional vascular
disorders. Mononuclear cells, including T cells, have recently received
attention as potential mediators of the vascular dysfunction associated
with atherosclerosis.22 Similarly, there
is evidence implicating lymphocytes in ischemic disorders,
including ischemia-reperfusion injury23 and
unstable angina.24 Likewise, T cells may contribute to the
pathogenesis of transplant rejection25 26 and
myocarditis.27 Therefore, the possibility exists that
VAP-1 is a major regulator of the lymphocyte recruitment that is
associated with these conditions and VAP-1 may be an important target
for therapeutic intervention in at least some of these
cardiovascular diseases.
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Future Directions
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The studies by Salmi et al
21 have shed new light on
the potential
physiological and pathological
significance of VAP-1 in inflammatory
and
cardiovascular diseases, but much of the evidence
implicating
this adhesion molecule in the process of lymphocyte
recruitment
in vivo remains circumstantial. Additional studies are
needed
to determine whether immunoneutralization of VAP-1 in vivo
alters
the trafficking of CD8
+ cells in different
regional vascular
beds. Similarly, mice that are either genetically
deficient
or overexpress VAP-1 should be developed and subsequently
used
to assess the importance of this adhesion molecule in lymphocyte
trafficking.
Both of these experimental strategies should reveal the
qualitative
and quantitative contributions of VAP-1 to the recruitment
of
lymphocytes in the healthy or inflamed microvasculature and
should
define the role of this adhesion molecule in immune function.
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Footnotes
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The opinions expressed in this editorial are not necessarily
those of the editors or of the American Heart Association.
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