BLR1 Ligand/ BCA-1/BLC

4 Pages·0.096 MB·English

by  Forster R.

BLR1 Ligand/
BCA-1/BLC
Reinhold Fo¨ rster*
Molecular Tumor Genetics and Immunogenetics, Max-Delbruck-Center for Molecular Medicine,
Robert Rossle Street 10, Berlin, 13092, Germany
*corresponding author tel:[phone], fax:[phone], e-mail: [email protected]
DOI: 10.1006/rwcy.2000.10011.
SUMMARY indicates that this chemokine is the major regulator
of B cell migration to and within lymphoid follicles
in most secondary lymphoid organs during normal
The CXC chemokine BLC/BCA-1 is constitutively
immune surveillance.
expressedinlymphoidfolliclesofsecondarylymphoid
organs. It binds to the chemokine receptor CXCR5,
which is found on mature B cells and a small sub-
Alternative names
population of T memory cells. By attracting B cells,
BLC/BCA-1 essentially contributes to B cell homing
BLR1 ligand
andproperpositioningofthesecellswithinthemicro-
anatomic compartments of secondary lymphoid
organs.
GENE AND GENE REGULATION
BACKGROUND Accession numbers
Discovery
GenBank/EMBL:
Human BLC/BCA-1: AF044197, AJ002211
Two groups succeeded in identifying a novel member Mouse BLC/BCA-1: AF044196
of the CXC chemokine family by searching the EST DNA sequences used for cloning mouse BLC/
expressedsequencetag(EST)databasefortranscripts BCA-1: IMAGE Consortium Clone 596050
with sequence motifs characteristic for chemokines. EST DNA sequences used for cloning human BLC/
Since it strongly attracts B lymphocytes, this chemo- BCA-1:T39765,AA298459,T55152;sequence-tagged
kine has been termed B lymphocyte chemoattractant side (STS) for chromosomal localization of human
(BLC) (Gunn et al., 1998) and B cell-attracting BLC/BCA-1: G14456
chemokine (BCA) 1 (Legler et al., 1998). Both mig-
ration and calcium mobilization assays demonstrate
Chromosome location
that BLC/BCA-1 specifically bindsto an orphanche-
mokine receptor formerly known as BLR1 (Dobner
et al., 1992). In accordance with the current nomen- The human BLC/BCA-1 gene is located on chromo-
clature, BLR1 was consequently termed CXCR5. some 4q21 and is thus in close proximity to most
BLC/BCA-1 is constitutively expressed in the B cell- CXC chemokines including IL-8, GRO, and IP-10.
rich zone of most secondary lymphoid organs. This The cDNA contains an open reading frame of 327
finding, together with the characteristic phenotype nucleotides encoding a putative protein of 109 amino
of CXCR5-gene targeted mice (Fo¨rster et al., 1996), acids with a predicted leader sequence consisting of
1126 Reinhold Fo¨rster
21 and 22 amino acids in mice and humans respec- Important homologies
tively. In both species, the secreted protein contains
four cysteines at positions characteristic for members
Theaminoacidsimilaritybetweenhumanandmurine
of the CXC chemokine family. Expression of BLC/
BLC/BCA-1 is 64% as compared with 24–34% for
BCA-1 has been identified in spleen, lymph nodes,
otherCXCchemokines.Interestingly,aproteincoded
Peyer’s patches, and liver (Gunn et al., 1998; Legler
for by Mareks disease virus (MDV), Meq-sp, shows
et al., 1998).
the highest similarity to human and murine BLC/
BCA-1. MDV, a lymphotropic herpesvirus, causes a
Relevant linkages lethaldiseaseinchickenswhichischaracterizedbyan
initial lytic infection of B cells and the subsequent
development of T cell lymphomas (Gunn et al., 1998;
CXCR5.
Legler et al., 1998).
PROTEIN
CELLULAR SOURCES AND
Accession numbers TISSUE EXPRESSION
Cellular sources that produce
Mouse BLC/BCA-1: AF044196
Human BLC/BCA-1: AF044197, AJ002211
Northern blot analysis demonstrates that expression
of BLC/BCA-1 is restricted to the liver and to
Sequence
secondary lymphoid organs such as spleen, lymph
nodes,andappendix.Incontrast,noexpressioncould
See Figure 1. beobservedinthethymusandthebonemarroworby
any nonlymphoid organs (Gunn et al., 1998; Legler
et al., 1998). In situ hybridization reveals that this
Description of protein
chemokine is expressed in a reticular pattern. In the
spleen it is expressed in the B cell follicles and at
BasedoncDNAanalysis,anopenreadingframethat the marginal zone. In Peyer’s patches, expression is
encodes a putative protein of 109 amino acids has greatest in the germinal centers, but also extends into
been identified in mice and humans. Murine BLC/ the surrounding mantle zone. A similar expression
BCA-1 contains a predicted leader peptide of 21 pattern could be observed in lymph nodes but,
amino acids, whereas in humans a predicted leader interestingly,expressionisvariableandnotseeninall
peptide of 22 amino acids has been found. Thus the follicles (Gunn et al., 1998). The reticular expression
predictedsecretedproteinconsistsof88(murine)and patternandthefollicularlocalizationstronglysuggest
87 (human) amino acids. that follicular dendritic cells (FDCs) may be a source
Figure 1 Alignment of the protein sequence of murine and human BLC/BCA-1. The
putative leader sequences are underlined. Identical amino acids are indicated by asterisks.
Sequence
Human BLC/BCA-1:
SIVCVDPQAEWIQRMMEVLRKRSSSTLPVPVFKRKIP
VLEVYYTSLRCRCVQESSVFIPRRFIDRIQILPRGNGCPRKEIIVWKKNK
BLR1 Ligand/BCA-1/BLC 1127
of this chemokine. Expression of BLC/BCA-1 is constitutive expression of BLC/BCA-1 in lymphoid
strongly reduced in the spleen of RAG1-deficient follicles and its marked chemotactic activity towards
mice.Astheseanimalsaredeficientinlymphocytes,it Bcells,itseemslikelythatBLC/BCA-1contributesto
seems likely that lymphocytes provide a signal that the development of B cell areas in some secondary
stimulates constitutive expression of BLC/BCA-1 in lymphoid organs. This view is supported by the
nonlymphoid cells of the spleen and other lymphoid observedphenotypeofgene-targetedmicelackingthe
organs. chemokine receptor CXCR5. These animals show
morphologically altered B cell follicles and impaired
B cell migration in spleen and Peyer’s patches
RECEPTOR UTILIZATION (Fo¨rster et al., 1996).
CXCR5 is the only receptor for BLC/BCA-1
identified so far. References
Barella, L., Loetscher, M., Tobler, A., Baggiolini, M., and
IN VITRO ACTIVITIES Moser, B. (1995). Sequence variation of a novel heptahelical
leucocyte receptor through alternative transcript formation.
Biochem.J.309,773–779.
In vitro findings
Dobner, T., Wolf, I., Emrich, T., and Lipp, M. (1992).
Differentiation-specificexpressionofanovelGprotein-coupled
InvitromigrationassayshaveshownthatBLC/BCA- receptorfromBurkitt’slymphoma.Eur.J.Immunol.22,2795–
2799.
1attractsBlymphocyteswithhighefficacy.However,
Fo¨rster,R.,Mattis,E.A.,Kremmer,E.,Wolf,E.,Brem,G.,and
as high concentrations of the chemokine (1mM) are
Lipp,M.(1996).Aputativechemokinereceptor,BLR1,directs
needed to induce maximal migration, it has relatively B cell migration to defined lymphoid organs and specific
low potency. Compared with the potent effect ob- anatomiccompartmentsofthespleen.Cell87,1037–1047.
servedonBcells,BLC/BCA-1inducesaweakchemo- Fo¨rster, R., Emrich, T., Kremmer, E., and Lipp, M. (1994).
Expression of the G-protein-coupled receptor BLR1 defines
tactic response in T cells and macrophages, but is
mature recirculating B cells and a subset of T memory helper
completelyinactiveonneutrophils(Gunnetal.,1998;
cells.Blood84,830–840.
Legler et al., 1998). The differential responsiveness Gunn, M. D., Ngo, V. N., Ansel, K. M., Ekland, E. H.,
ofdefinedleukocytesubsetstostimulationwithBLC/ Cyster, J. G., and Williams, L. T. (1998). A B-cell homing
BCA-1 correlates with the expression pattern of chemokine made in lymphoid follicles activates Burkitt’s lym-
phomareceptor-1.Nature391,799–803.
CXCR5.Thischemokinereceptorhasbeenidentified
Kaiser,E.,Fo¨rster,R.,Wolf,I.,Ebensperger,C.,Kuehl,W.M.,
on mature B cells and small subsets of CD4+ and
andLipp,M.(1993).TheGprotein-coupledreceptorBLR1is
CD8+Tcells(Dobneretal.,1992;Kaiseretal.,1993; involvedinmurineBcelldifferentiationandisalsoexpressedin
Fo¨rster et al., 1994) and as a variant form on mono- neuronaltissues.Eur.J.Immunol.23,2532–2539.
cytes (Barella et al., 1995). Upon stimulation with Legler, D. F., Loetscher, M., Roos, R. S., Clark-Lewis, I.,
Baggiolini,M., and Moser, B. (1998). B cell-attracting chemo-
BLC/BCA-1, CXCR5-transfected cells respond with
kine1,ahumanCXCchemokineexpressedinlymphoidtissues,
a transient rise of intracellular (Ca2+). In contrast,
selectively attracts B lymphocytes via BLR1/CXCR5. J. Exp.
peripheral blood B cells do not respond with Med.187,655–660.
intracellular Ca2+ mobilization when activated with
this chemokine. This observation suggests that
chemokine receptors might couple to different sig-
LICENSED PRODUCTS
naling pathways in B cells compared with other
leukocytes.
Recombinant proteins are available from R&D
Systems and Peprotech.
IN VIVO BIOLOGICAL
ACTIVITIES OF LIGANDS IN
ANIMAL MODELS
Normal physiological roles
The biological activities of this chemokine have
not yet been studied in vivo. However, based on