By
From the * Laboratory of Molecular Genetics and Immunology, The Rockefeller University,
New York 10021; the Medical Research Council Laboratory for Molecular Cell Biology and
Department of Biochemistry, University College London, London WC1E 6BT, United Kingdom; and
the § Department of Molecular Genetics, Kansai Medical University, Moriguchi, Osaka 570, Japan
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The entry of B lymphocytes into secondary lymphoid organs is a critical step in the development
of an immune response, providing a site for repertoire shaping, antigen-induced activation and selection. These events are controlled by signals generated through the B cell antigen receptor
(BCR) and are associated with changes in the migration properties of B cells in response to
chemokine gradients. The chemokine stromal cell-derived factor (SDF)-1 is thought to be one
of the driving forces during those processes, as it is produced inside secondary lymphoid organs
and induces B lymphocyte migration that arrests upon BCR engagement. The signaling pathway that mediates this arrest was genetically dissected using B cells deficient in specific BCR-coupled signaling components. BCR-induced inhibition of SDF-1
chemotaxis was dependent on Syk, BLNK, Btk, and phospholipase C (Plc)
2 but independent of Ca2+ mobilization,
suggesting that the target of BCR stimulation was a protein kinase C (PKC)-dependent substrate. This target was identified as the SDF-1
receptor, CXCR4, which undergoes PKC- dependent internalization upon BCR stimulation. Mutation of the internalization motif SSXXIL
in the COOH terminus of CXCR4 resulted in B cells that constitutively expressed this receptor
upon BCR engagement. These studies suggest that one pathway by which BCR stimulation results in inhibition of SDF-1
migration is through PKC-dependent downregulation of CXCR4.
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The ability to successfully mount an immune response depends on the interaction of multiple cell types, insuring that autoreactivity is avoided, diversity and specificity are achieved, and a memory of the encounter is established. The anatomic compartmentalization of APCs, T and B lymphocytes, and effector cells in secondary lymphoid organs like the spleen or lymph node maximizes the probability of interaction of the cellular and humoral factors necessary to achieve these responses. Zones containing specific cellular populations allow ordered and sequential interactions to take place, thereby insuring that only a small subset of B lymphocytes are stimulated and produce antibody or undergo further somatic hypermutation within germinal centers (GCs)1 (1, 2). Although important during an immune response, changes in the migration and position of B cells inside lymphoid organs are also intimately associated with their stage of maturation. An antigen receptor (AgR)-dependent positive selection process allows some of the newly generated bone marrow B cells to progress to the mature B cell stage. This selection event is associated with follicular relocalization. In those sites, in contact with follicular dendritic cells, B lymphocytes might receive survival signals and become recruited to the long-lived B cell repertoire (3).
Above a threshold of AgR engagement, B cells migrate toward or arrest within the periarteriolar lymphoid sheath, where the probability of encountering Ag-specific T cells is maximal. In the absence of cognate interactions with T cells, activated B cells will die, and as a consequence, strong autoreactivity will be purged from the repertoire (6, 7). Rare activated B cells that receive cognate T cell help will proliferate, and some of them will join follicles to form GCs. The GC reaction generates B cells with new migration properties. Thus, plasmocytes can relocate into the red pulp of the spleen, join the peripheral circulation, and enter the bone marrow, where they will produce antibody for an extended period of time (8). Memory B cells will either recirculate or reside in the marginal zone of the spleen, the privileged area for reencounter with blood-borne antigen (1).
Four chemokines with the ability to direct the migration
of B lymphocytes are known to be expressed within secondary lymphoid organs. These are B lymphocyte chemoattractant (BLC) (or B cell-attracting chemokine [BCA]-1),
which binds to the Burkitt's lymphoma receptor 1 (BLR1)
(or CXCR5) (9, 10); secondary lymphoid tissue chemokine (SLC, or 6C-kine, exodus-2) and Epstein-Barr virus-
induced molecule 1 ligand chemokine (ELC, or MIP3),
both binding to the chemokine receptor CCR7 (11, 12); and
SDF-1
(or pre-B cell growth-stimulating factor [PBSF]),
which stimulates cells through CXCR4 (13, 14). The importance of these chemokines in the migration and selection processes is suggested either by the differential expression of their receptors during B cell maturation or by the fact that
AgR engagement can modulate the associated chemotactic
responses. BLR1, the receptor for BLC, is only expressed
when cells mature from newly generated to follicular B cells;
this expression is likely to account, at least in part, for the
tropism of those cells for follicles. Thus, inactivation of
BLR1 by targeted gene disruption is associated with deficits
in spleen and Peyer's patch follicles (15, 16). BCR activation
has a direct impact on B cell chemotaxis to ELC and SDF-1
, resulting in either enhancement or arrest, respectively
(12, 14). Given that AgR signaling controls B cell maturation and is associated with cell relocalization, the direct regulation of chemokine responsiveness by BCR engagement is
likely to play a major role in driving the selection and organization of B lymphocytes within lymphoid organs.
The mechanism by which BCR ligation may lead to
SDF-1 unresponsiveness has been addressed in this study
by using the genetically defined DT40 B cell system. Targeted disruption of many of the signaling components of
the BCR-stimulated pathway have been generated in these
cells and have demonstrated great utility in defining the
mechanisms by which antigen stimulation of B cells results in cellular activation. DT40 B cells migrate efficiently to
SDF-1
and are arrested in their migration by BCR cross-linking. Through the analysis of a series of signaling mutants of DT40 cells, we have established that BCR stimulation results in a calcium-independent, protein kinase C
(PKC)-dependent downregulation of the SDF-1
receptor
CXCR4. These studies suggest mechanisms by which diverse signals may influence this pathway and thereby modulate redirected migration of B cells inside lymphoid tissues.
![]() |
Materials and Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Reagents.
Human SDF-1DT40 Cell Culture and Transfections.
Wild type (wt) and Btk- (18), Syk- (19), phospholipase C (Plc)Chemotaxis Assay.
DT40 cells (106 cells per condition) were washed and resuspended in 100 ml RPMI 1640 and 0.25% HSA and incubated for 1 h at 39°C in the presence of different concentrations of anti-BCR antibodies. Cells were then added to the top chamber of a 6.5-mm diameter, 5-µm pore polycarbonate transwell culture insert (Costar Corp.); the lower chamber contained RPMI 0.25% HSA alone or supplemented with 100 nM SDF-1CXCR4 Surface Expression Analysis.
Cells expressing wt or the 4A mutant of human CXCR4 were resuspended in RPMI 1640 and 0.25% HSA at 107 cells/ml. They were then diluted twice with the same buffer or with medium supplemented with 200 nM SDF-1
|
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
To determine if the chicken B cell line
DT40 was an accurate model for SDF-1-dependent migration and BCR-induced arrest, we characterized the ability of these cells to migrate in response to this chemokine.
DT40 cells were placed on the upper side of a transwell
apparatus, and human SDF-1
was placed on the opposite side. DT40 cells migrated efficiently (Fig. 1) to this chemokine. The migration was specifically inhibited by anti-
SDF-1
antibody but not by an irrelevant antibody (not
shown), demonstrating the specificity of this migration effect. Cross-linking of the BCR on DT40 cells with the
murine mAb M4 for 1 h resulted in a dose-dependent inhibition of SDF-1
-mediated migration, resulting in full inhibition at 5 µg/ml. The ability of this chicken cell line to
respond to the human chemokine further confirms that
SDF-1
and its receptor are highly conserved among diverse species. Although the chicken version of SDF-1
and
its receptor have not been characterized, it is likely that a
high degree of sequence conservation will be found for this
species as well.
|
A series of homozygous cell
lines deficient in specific BCR signaling components has
been generated in DT40 cells (18). These mutant lines
were tested for their ability to migrate in response to SDF-1
and to arrest upon BCR cross-linking. As seen in Fig. 2, all
of the mutants tested, whether deficient in either early
(syk) or late (Btk, BLNK, Plc
2, IP3R) components of
BCR-induced signaling, migrated in response to SDF-1
.
In contrast, the BCR-induced arrest of SDF-1
-directed
migration was observed in some, but not all, of the mutants
tested. Although cells deficient for molecules involved in
Plc
2 activation such as syk, BLNK, Btk, and Plc
2 were
unable to mediate BCR-induced arrest of SDF-1 migration, IP3R-deficient cells (generated by deletion of the
three IP3 receptor genes) retained their ability to migrate in
response to SDF-1
and arrest upon BCR cross-linking.
DT40 cells have three IP3 receptors that mediate the efflux
of calcium from intracellular stores in response to IP3 (22).
A triple knockout of these receptors is unable to trigger intracellular calcium release in response to BCR-induced IP3
stimulation yet maintains its ability to arrest SDF-1
-mediated migration. IP3 and diacylglycerol are both produced in
response to Plc
2 activation. As BCR-induced arrest is
Plc
2 dependent but IP3R independent, it implies that the
pathway triggered by Plc
2, which is affected in BCR-
induced arrest of SDF-1
migration, is diacylglycerol dependent, which, in turn, activates PKC. Thus, the dependence
on Plc
2 in the absence of IP3-stimulated release of calcium implies that the mechanism by which BCR cross-linking results in migration arrest to SDF-1
may be dependent upon PKC activation through Plc
2.
|
One mechanism by
which BCR activation could lead to arrest of SDF-1-
mediated migration might result from BCR-induced downregulation of the SDF-1
receptor from the cell surface by
a PKC-dependent internalization of the SDF-1
receptor.
Previous studies have demonstrated that the SDF-1 receptor,
CXCR4, is rapidly internalized upon activation of PKC by
phorbol esters that, in turn, can be blocked by inhibitors of
PKC (25, 26). To determine if a BCR-induced, PKC-
dependent internalization of the CXCR4 pathway is present in DT40 cells, the human SDF-1
receptor, CXCR4, was
stably transfected into wt and Plc
2-mutant DT40 cells.
Cell surface expression of human CXCR4 on DT40 cells is
downregulated in response to BCR cross-linking, phorbol
ester treatment, or SDF-1
exposure (Fig. 3). However,
BCR-induced downregulation of CXCR4 is blocked in the Plc
2-deficient DT40 background, which correlates
with the inability of this mutant to display BCR-mediated
arrest of SDF-1
migration. To determine if Plc
2 is upstream, downstream, or pleiotropic in relation to CXCR4,
this mutant was tested for its ability to respond to phorbol
esters or SDF-1
. CXCR4 surface expression is downregulated normally in Plc
2-deficient cells in response to
phorbol esters or SDF-1
(Fig. 3), indicating that Plc
2 lies upstream of CXCR4 in the BCR-induced internalization
pathway and that SDF-1
-induced internalization is independent of Plc
2 activation. These results thus suggest that
the BCR-induced arrest of SDF-1
-directed migration
may be due in part to CXCR4 internalization triggered by
BCR-mediated stimulation of Plc
2 and PKC activation.
In addition, they show that SDF-1
and BCR activation
lead to CXCR4 surface downregulation through different
pathways in DT40 B cells.
Signoret
et al. (23) have demonstrated that a SSXXIL motif, similar
to that required for endocytosis of CD4 and the TCR complex, is required for phorbol ester-induced, but not
ligand-induced, internalization of CXCR4. To determine
the contribution of this motif to the BCR-induced internalization of CXCR4 in DT40 cells, we generated stable
transfectants of DT40 wt or Plc2-mutant cells expressing
a CXCR4 mutant in which the SSLKIL sequence was replaced by AALKAA. As seen in Figs. 3 and 4, wt DT40
cells expressing the wt human CXCR4 receptor internalize
this receptor in response to BCR cross-linking, SDF-1
treatment, and PMA stimulation. In contrast, the SSLKIL
AALKAA mutant CXCR4 receptor (designated 4A in Fig.
4), whether expressed in wt or Plc
2-mutant DT40 cells, was incapable of BCR- or PMA-induced internalization
(Fig. 4) but retained significant receptor downmodulation
in response to SDF-1
. The 4A mutant CXCR4 was unable to migrate in response to SDF-1
, either in the presence or absence of BCR cross-linking (data not shown).
The basis for this migration defect has not been determined.
BCR- and Plc
2-dependent internalization of CXCR4 thus appears to utilize the same pathway as PMA, a PKC-dependent downmodulation of this receptor.
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
AgR signaling determines B cell maturation, selection, and orientation within lymphoid organs. Progression from newly generated B cells into MZ and follicular B cells is driven by BCR signaling and is associated with specific anatomic localization inside the spleen. Supra-threshold AgR engagement redirects B cells from follicles, MZ, or blood circulation toward the periarteriolar lymphoid sheath. Depending on their ability to direct cognate interaction with T cells, a humoral response will emerge or B cells will die in a few days (2, 5, 6, 27).
It is now clearly established that chemokines play an important role in these relocalization processes. Thus, the expression of BLR1 is associated with follicular B cell maturation and is required for their tropism in the spleen and
Peyer's patch, whereas SDF-1 and SLE responses are rapidly regulated upon BCR engagement (12, 14, 16). The
BCR-induced downregulation of CXCR4 demonstrated here offers a first example in which differential AgR engagement might promote differential responsiveness to a
chemokine and allow repertoire-based interclonal competition for migration toward a restricted, chemokine-secreting environment (28). However, as seen in Fig. 3, BCR
cross-linking results in a twofold reduction in CXCR4 expression. Although this change in expression may account for some of the migration inhibition seen, it suggests that
other pathways may be involved as well. The generation
of CXCR4 mutants that are deficient in BCR-induced
downregulation yet retain chemotactic response to SDF-1
will allow further dissection of the contribution of this
pathway to the antigen-driven compartmentalization of lymphocytes. In addition, the definition of SDF-1
secretion sites will provide important clues toward the understanding of B cell migration and selection.
In vitro studies have shown that pro-B cells are dependent on contact with stromal cells and cytokines for survival, whereas cells expressing the pre-B cell receptor are
only dependent on soluble factors (29, 30). Bone marrow
stromal cells produce SDF-1, and pro-B cells respond to
this chemokine (13, 31). It is tempting to transpose our
data from the early steps of pro-B to pre-B cell transition.
Thus, like BCR, pre-BCR signaling might induce the
downregulation of CXCR4 and block SDF-1
-dependent migration of pre-B cells toward stromal cells. Therefore,
CXCR4 downregulation might allow B cells to lose stromal cell tropism upon successful rearrangement of their
IgH gene and signaling through the pre-B cell receptor.
This mechanism could guarantee the restriction of rare
niches to pro-B cells. In agreement with the importance of
SDF-1 during early B cell differentiation, SDF-1 and
CXCR4 knockout mice show a profound defect in pro-B
cell production (32). The present definition of a pathway from BCR to the CXCR4 receptor and of a motif responsible for this coupling may allow the construction of
mutants to directly test the role of this pathway in vivo.
Such analysis might provide insights that will define how
Ag-dependent competitive migration participates in B cell
maturation and response to Ag.
![]() |
Footnotes |
---|
Address correspondence to Jeffrey V. Ravetch, Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Ave., New York, NY 10021. Phone: 212-327-7321; Fax: 212-327-7319; E-mail: ravetch{at}rockvax.rockefeller.edu
Received for publication 18 February 1999 and in revised form 15 March 1999.
This work was supported in part by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); the National Institute of Allergy and Infectious Diseases, NIH; the Irvington Institute for Immunological Research; and the Association pour la Recherche contre le Cancer.
Abbreviations used in this paper BLR1, Burkitt's lymphoma receptor 1; GCs, germinal centers; HSA, human serum albumin; PKC, protein kinase C; Plc, phospholipase C; wt, wild type.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1. | Liu, Y.J., J. Zhang, P.J. Lane, E.Y. Chan, and I.C. MacLennan. 1991. Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. Eur. J. Immunol. 21: 2951-2962 [Medline]. |
2. | MacLennan, I.C., Y.J. Liu, and G.D. Johnson. 1992. Maturation and dispersal of B-cell clones during T cell-dependent antibody responses. Immunol. Rev. 126: 143-161 [Medline]. |
3. | Gu, H., D. Tarlinton, W. Muller, K. Rajewsky, and I. Forster. 1991. Most peripheral B cells in mice are ligand selected. J. Exp. Med. 173: 1357-1371 [Abstract]. |
4. | Lortan, J.E., C.A. Roobottom, S. Oldfield, and I.C. MacLennan. 1987. Newly produced virgin B cells migrate to secondary lymphoid organs but their capacity to enter follicles is restricted. Eur. J. Immunol. 17: 1311-1316 [Medline]. |
5. | Goodnow, C.C., J.G. Cyster, S.B. Hartley, S.E. Bell, M.P. Cooke, J.I. Healy, S. Akkaraju, J.C. Rathmell, S.L. Pogue, and K.P. Shokat. 1995. Self-tolerance checkpoints in B lymphocyte development. Adv. Immunol. 59: 279-368 [Medline]. |
6. | Fulcher, D.A., A.B. Lyons, S.L. Korn, M.C. Cook, C. Koleda, C. Parish, D.S. Fazekas, and A. Basten. 1996. The fate of self-reactive B cells depends primarily on the degree of antigen receptor engagement and availability of T cell help. J. Exp. Med. 183: 2313-2328 [Abstract]. |
7. | Cyster, J.G., S.B. Hartley, and C.C. Goodnow. 1994. Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire. Nature. 371: 389-395 [Medline]. |
8. | Slifka, M.K., R. Antia, J.K. Whitmire, and R. Ahmed. 1998. Humoral immunity due to long-lived plasma cells. Immunity. 8: 363-372 [Medline]. |
9. | Gunn, M.D., V.N. Ngo, K.M. Ansel, E.H. Ekland, J.G. Cyster, and L.T. Williams. 1998. A B-cell-homing chemokine made in lymphoid follicles activates Burkitt's lymphoma receptor-1. Nature. 391: 799-803 [Medline]. |
10. | Legler, D.F., M. Loetscher, R.S. Roos, I. Clark-Lewis, M. Baggiolini, and B. Moser. 1998. B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J. Exp. Med. 187: 655-660 [Abstract/Full Text]. |
11. | Gunn, M.D., K. Tangemann, C. Tam, J.G. Cyster, S.D. Rosen, and L.T. Williams. 1998. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Nature. 391: 799-803 [Medline]. |
12. | Ngo, V.N., H.L. Tang, and J.G. Cyster. 1998. Epstein-Barr virus-induced molecule 1 ligand chemokine is expressed by dendritic cells in lymphoid tissues and strongly attracts naive T cells and activated B cells. J. Exp. Med. 188: 181-191 [Abstract/Full Text]. |
13. | Bleul, C.C., R.C. Fuhlbrigge, J.M. Casasnovas, A. Aiuti, and T.A. Springer. 1996. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J. Exp. Med. 184: 1101-1109 [Abstract]. |
14. | Bleul, C.C., J.L. Schultze, and T.A. Springer. 1998. B lymphocyte chemotaxis regulated in association with microanatomic localization, differentiation state, and B cell receptor engagement. J. Exp. Med. 187: 753-762 [Abstract/Full Text]. |
15. | Schmidt, K.N., C.W. Hsu, C.T. Griffin, C.C. Goodnow, and J.G. Cyster. 1998. Spontaneous follicular exclusion of SHP1-deficient B cells is conditional on the presence of competitor wild-type B cells. J. Exp. Med. 187: 929-937 [Abstract/Full Text]. |
16. | Forster, R., A.E. Mattis, E. Kremmer, E. Wolf, G. Brem, and M. Lipp. 1996. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell. 87: 1037-1047 [Medline]. |
17. | Ono, M., H. Okada, S. Bolland, S. Yanagi, T. Kurosaki, and J.V. Ravetch. 1997. Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Cell. 90: 293-301 [Medline]. |
18. |
Takata, M., and
T. Kurosaki.
1996.
A role for Brutons tyrosine kinase in B cell antigen receptor-mediated activation
of phospholipase C![]() |
19. | Kurosaki, T., S.A. Johnson, L. Pao, K. Sada, H. Yamamura, and J.C. Cambier. 1995. Role of the Syk autophosphorylation site and SH2 domains in B cell antigen receptor signaling. J. Exp. Med. 182: 1815-1823 [Abstract]. |
20. |
Takata, M.,
Y. Homma, and
T. Kurosaki.
1995.
Requirement of phospholipase C![]() |
21. |
Ishiai, M.,
M. Kurosaki,
R. Pappu,
K. Okawa,
I. Ronko,
C. Fu,
M. Shibata,
A. Iwamatsu,
A.C. Chan, and
T. Kurosaki.
1999.
BLNK required for coupling Syk to PLC![]() |
22. | Sugawara, H., M. Kurosaki, M. Takata, and T. Kurosaki. 1997. Genetic evidence for involvement of type 1, type 2 and type 3 inositol 1,4,5-triphosphate receptors in signal transduction through the B-cell antigen receptor. EMBO (Eur. Mol. Biol. Organ.) J. 16: 3078-3088 [Abstract/Full Text]. |
23. | Signoret, N., M.M. Rosenkilde, P.J. Klasse, T.W. Schwartz, M.H. Malim, J.A. Hoxie, and M. Marsh. 1998. Differential regulation of CXCR4 and CCR5 endocytosis. J. Cell Sci. 111: 2819-2830 [Abstract]. |
24. | Morgenstern, J.P., and H. Land. 1990. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 18: 3587-3596 [Abstract]. |
25. |
Amara, A.,
S.L. Gall,
O. Schwartz,
J. Salamero,
M. Montes,
P. Loetscher,
M. Baggiolini,
J.L. Virelizier, and
F. Arenzana-Seisdedos.
1997.
HIV coreceptor downregulation as antiviral
principle: SDF-1![]() |
26. | Signoret, N., J. Oldridge, A. Pelchen-Matthews, P.J. Klasse, T. Tran, L.F. Brass, M.M. Rosenkilde, T.W. Schwartz, W. Holmes, W. Dallas, et al . 1997. Phorbol esters and SDF-1 induce rapid endocytosis and downmodulation of the chemokine receptor CXCR4. J. Cell Biol. 139: 651-664 [Abstract/Full Text]. |
27. | Chen, X., F. Martin, K.A. Forbush, R.M. Perlmutter, and J.F. Kearney. 1997. Evidence for selection of a population of multi-reactive B cells into the splenic marginal zone. Int. Immunol. 9: 27-41 [Abstract]. |
28. | Goodnow, C.C., and J.G. Cyster. 1997. Lymphocyte homing: the scent of a follicle. Curr. Biol. 7: R219-R222 [Medline]. |
29. | Melchers, F., A. Strasser, S.R. Bauer, A. Kudo, P. Thalmann, and A. Rolink. 1989. Cellular stages and molecular steps of murine B-cell development. Cold Spring Harb. Symp. Quant. Biol. 1: 183-189 . |
30. | Hardy, R.R., C.E. Carmack, S.A. Shinton, J.D. Kemp, and K. Hayakawa. 1991. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J. Exp. Med. 173: 1213-1225 [Abstract]. |
31. | D'Apuzzo, M., A. Rolink, M. Loetscher, J.A. Hoxie, I. Clark-Lewis, F. Melchers, M. Baggiolini, and B. Moser. 1997. The chemokine SDF-1, stromal cell-derived factor 1, attracts early stage B cell precursors via the chemokine receptor CXCR4. Eur. J. Immunol. 27: 1788-1793 [Medline]. |
32. | Tachibana, K., S. Hirota, H. Iizasa, H. Yoshida, K. Kawabata, Y. Kataoka, Y. Kitamura, K. Matsushima, N. Yoshida, S. Nishikawa, et al . 1998. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature. 393: 591-594 [Medline]. |
33. | Zou, Y.R., A.H. Kottmann, M. Kuroda, I. Taniuchi, and D.R. Littman. 1998. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature. 393: 595-599 [Medline]. |
34. | Nagasawa, T., S. Hirota, K. Tachibana, N. Takakura, S. Nishikawa, Y. Kitamura, N. Yoshida, H. Kikutani, and T. Kishimoto. 1996. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature. 382: 635-638 [Medline]. |