Research Report 2000 - MDC

Role of lysosphingophospholipid
receptors in the immune system
We have cloned human EDG6 from in
vitro differentiated dendritic cells in
order to identify novel G proteincoupled
receptors (GPCR) that control
immune functions. EDG6-specific
RNA was detected almost exclusively
in lymphoid and hematopoietic tissue,
and in lung. Moreover the expression
pattern of EDG6 was found to be
conserved in mouse and man.
Homology of EDG-6 to the recently
identified sphingosine-1-phosphate
(SPP) receptors EDG-1, -3 and -5 and
lysophosphatidic acid (LPA) receptors
EDG-2 and -4. suggests that its ligand
may be a lysophospholipid or
lysosphingolipid. In collaboration
with S. Spiegel, Washington, we have
shown that EDG-6 is a high affinity
receptor for SPP which couples to a
G i/o protein resulting in the activation
of growth-related signaling pathways.
Although the biological significance
of SPP signaling via EDG-6 in
lymphocytes and dendritic cells is
70
Spleen
PP
LN ?
maturation
& migration
CXCR5
iDC
ELC
CXCR5
B
B
(skin)
immature antigencapturing
LC
DC
T
CCR7
T
T T T
B B
LTα1β2 LTβR
CCR7
CCR7
poorly understood, the well
characterized growth-related or
cytoskeleton-associated activities of
SPP suggest that members of the EDG
family may synergize with signaling
pathways initiated by cytokines.
Lysosphingophospholipids may play a
critical role as potent autocrine and
paracrine mediators in specific microenvironmental
settings of normal and
pathophysiological immune responses.
Differentiation-specific
regulation and function of
CD155/poliovirus receptor
CD155, a transmembrane protein
possessing an Ig-like architecture, was
discovered originally by its ability to
serve as the cellular receptor for
poliovirus (PV). Since then, a lot of
effort has been devoted to elucidate
the involvement of CD155 in PV
infection, a complicated series of
events with the potential outcome of
the poliomyelits syndrome in affected
individuals. However, there is no
CCR7
afferent
lymphatic vessels
CXCR5
B
FDC
HEV
SLC
SLC
peripheral
tissue
B
BLC
stromal
cells
T
T
stromal
cells
CCR7
T
efferent
lymphatic vessels
B zone
T
information about the natural function
of CD155 and, so, we initiated studies
I) to investigate the expression profile
of CD155 (by means of analysing the
promoter of the CD155 gene) and II)
to identify counter receptors/ligands
of CD155. Our findings suggest that
CD155 is one of the cell adhesion
class of molecules since it interacts
with vitronectin and, to a lesser
extent, with fibronectin. Currently, we
are investigating these interactions in
more detail. Interestingly,
immunohistochemical studies have
shown that expression of vitronectin
and CD155 colocalizes to the
germinal centers of secondary
lymphoid tissue.
Figure 28: Lessons from chemokine receptor
knock outs: Model of chemokine-directed
trafficking of lymphocytes and dendritic cells to
and through secondary lymphoidorgans during
the immune response.