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5, v, and 4 Integrins1
*
Howard Hughes Medical Institute, Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139;
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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5,
V, or 4 were used to dissect the in vivo
roles of these adhesion receptors during leukocyte development and
traffic. No major defects were observed in the development of
lymphocytes, monocytes, or granulocytes or in the traffic of
lymphocytes to different lymphoid organs in the absence of
5 or V integrins. However, in agreement
with previous reports, the absence of 4 integrins
produced major defects in development of lymphoid and myeloid lineages
and a specific defect in homing of lymphocytes to Peyer’s patches. In
contrast, the 4 integrin subunit is not essential for
localization of T lymphocytes into intraepithelial and lamina propria
compartments in the gut, whereas one of the partners of
4, the ß7 chain, has been shown to be
essential. However, 4-deficient T lymphocytes cannot
migrate properly during the inflammatory response induced by
thioglycolate injection into the peritoneum. Finally, in vitro
proliferation and activation of lymphocytes deficient for
5, V, or 4 integrins upon
stimulation with different stimuli were similar to those seen in
controls. These results show that integrins play distinct roles during
in vivo leukocyte development and traffic. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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5,
V, and 4 integrins
recognize different sites on fibronectin, and they also bind other
specific ligands, including vitronectin for V
integrins and VCAM-1 and mucosal addressin cell adhesion molecule-1
(MAdCAM-1)6 for
4 integrins (2, 3). Expression
studies have shown the presence of integrins on leukocyte progenitors
and their differential regulation among lineages (1, 4).
In particular, 4 and
5 integrins are expressed early during
hemopoietic development, but they are down-regulated during neutrophil
development. They are, however, expressed on mature lymphocytes,
monocytes, and granulocyte subsets. In contrast,
V integrins are expressed on specific T
lymphocyte subsets (
T cells) and on different leukocyte
precursors (data not shown), and V is
up-regulated during myeloid differentiation (5). The
functions of integrin receptors during leukocyte development in vivo,
however, have been unclear. In vitro studies have previously suggested
that 4 integrins participate in B lymphocyte
and myeloid development (6, 7). The expression of
4 and 5 integrins on
thymocytes is finely regulated, and this has also suggested a role for
these receptors during T lymphocyte differentiation (8).
However, little was known about the potential roles of
V integrins during these processes.
Lymphocytes exert their surveillance and activation functions thanks to
their continuous recirculation through lymphoid organs. The molecular
mechanisms involved in regulating these homing pathways are becoming
understood (9). The gut-associated lymphoid tissue in the
intestinal mucosa represents an integrated system of secondary lymphoid
organs, Peyer’s patches and mesenteric lymph nodes, and mucosal
effector sites, lamina propria (LP) and the intraepithelial lymphocyte
(IEL) compartment located above the villus basement membrane
(10). 4ß7
integrin is thought to confer gut tropism to lymphocytes because it is
expressed at high levels on a small subset of circulating memory T
cells (11, 12) that preferentially localize to Peyer’s
patches and to the intestinal LP (9). This selective
localization is mediated by its interaction with MAdCAM-1
(13), a molecule selectively expressed on intestinal
endothelial cells (14). The integrin
Eß7, expressed on a
subset of the
4ß7high
circulating T cells, on most IEL and on a substantial fraction of LP T
lymphocytes, mediates adhesion to E-cadherin expressed on epithelial
cells (15). Analyses of knockout and chimeric mice,
deficient in the expression of ß7 integrin or
its associated -chains (E and
4) have recently dissected some of the roles
of these adhesion receptors in constituting the lymphoid gut
compartment (15, 16, 17 ; for review, see Ref. 3).
In mice deficient for ß7 integrins, Peyer’s
patch formation was impaired, and reduced numbers of IEL and LP T cells
were observed. 4-integrin chimeric mice
confirmed the critical role of this subunit for homing of lymphocytes
to Peyer’s patches. In contrast, E-deficient
mice had normal Peyer’s patch size but reduced numbers of IEL and LP T
cells, suggesting its involvement in recruiting to these sites. The
roles of other integrin receptors, such as 5
and V integrins, have not been reported.
During the inflammatory response, lymphocytes initiate contact with the
activated endothelium, first by tethering and then by firm adhesion and
subsequent transmigration. Different adhesion receptors are involved in
regulating these steps, including selectins and integrins, particularly
4 and ß7 integrins,
and their ligands (3, 18). The role of
4 integrins in diverse inflammatory
pathologies has largely been investigated by blocking
4-mediated interactions with Abs or peptides,
and this approach is currently being used in clinical trials
(19). However, the direct in vivo roles that
4 integrins and other integrins, such as
5 and V, might play
in leukocyte transmigration during inflammatory processes have not yet
been analyzed.
Finally, signaling by integrins and other receptors is likely to play a role in lymphocyte activation (for review, see Refs. 20 and 21). Thus, integrin function is regulated by lymphocyte activation (4), and it has also been shown that several integrin ligands, including fibronectin and VCAM-1, can act as coactivation signals for lymphocytes (for review, see Ref. 21). Moreover, integrin receptors in lymphocytes can trigger multiple different signaling pathways. All these reports suggest that integrins might participate in lymphocyte activation. However, their roles in vivo are poorly defined.
To investigate the roles of 5,
V, and 4 integrins in
the development, homing, migration, and activation of lymphocytes in
vivo, analysis of mice lacking these receptors has been performed. To
circumvent the early lethality of 5-,
V-, and 4-null
embryos, chimeric mice were generated by injecting
5-, V-, or
4-null ES cells into blastocysts from
RAG-2-/- or C57BL6 mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Chimeric mice were generated by injection of
5-, V-, or
4-null or wild-type ES cells into blastocysts
from C57BL6 or RAG-2 deficient mice as previously described
(17). (For 5- and
4-null ES cells see Refs. 22 and
17 , respectively.) V-null ES
cells were obtained from heterozygous ES cell clones (23)
by selection in high concentration of G418 (3–4 mg/ml) as previously
described (24). Several independent
V-null ES cell clones were further analyzed
and used for chimeric studies and germline transmission experiments
(25). Mice were kept in the Massachusetts Institute of
Technology animal facility under clean conditions.
Flow cytometry
Anti-mouse mAbs from PharMingen were used for staining:
PE-conjugated anti-CD3-
(145-2C11), PE-conjugated anti-CD4
(L3T4, RM4-5), Cy-Chrome-conjugated anti-CD8 (Ly-2, 53-6.7),
PE-conjugated anti-CD45R/B220 (RA3-6B2), FITC-conjugated
anti-IgM (R6-60.2), PE- conjugated anti-CD11b (Mac-1
-chain, M1/70), PE-conjugated anti-Ly-6G (Gr-1, RB6-8C5),
FITC-conjugated anti-CD49d (integrin 4
chain, R1-2), FITC-conjugated anti-CD45.2 (Ly-5.2, 104),
FITC-conjugated anti-Ly-9.1 (30C7), PE-conjugated
anti-CD25/IL2-R (3C7), and PE-conjugated anti-CD69 (H1.2F3).
Single-cell suspensions obtained from thymus, bone marrow, spleen,
peritoneal lavage, and blood by routine dissection techniques were
incubated with purified anti-CD32/CD16 to block Fc receptors and
with an appropriate dilution of the different Abs at 4°C or room
temperature (blood samples). Samples were washed twice with PBS and
resuspended in PBS. Dead cells were excluded by propidium iodide
staining. Samples and data were analyzed in a FACScan using CellQuest
software (Becton Dickinson, Mountain View, CA).
Histology
Tissue specimens were fixed overnight in 4% formaldehyde and embedded in paraffin. Blocks were cut, and slides were processed and stained with hematoxylin-eosin by routine techniques. Slides were examined and photographed (Ektachrome 160T film; Eastman Kodak, Rochester, NY) with an Axiophot microscope (Carl Zeiss, New York, NY).
Immunohistochemistry
For immunohistochemistry, 6-µm cryostat-cut jejunal tissue sections were stained using the avidin-biotin-immunoperoxidase method according to the manufacturer’s instructions (Vector Laboratories, Burlingame, CA) using the anti-CD3 mAb 145-2C11 (Armenian hamster anti-mouse) or a nonbinding control Armenian hamster IgG, biotinylated goat anti-Armenian hamster (Jackson ImmunoResearch Laboratories, West Grove, PA), and then the avidin-biotin-immunoperoxidase elite reagent with 3-amino-9-ethylcarbazole as chromogen. Sections were counterstained with hematoxylin and anti-CD3-stained cells were quantitated as IEL per 1000 epithelial cells or as LP T cells per 0.5 mm villus length. The observer was blinded with respect to the tissue source during cell number quantitation.
Thioglycolate-induced peritonitis
Injection of 3% thioglycolate broth into the peritoneum of 8-
to 12-wk-old 4- or control-C57BL6 chimeric
mice was performed. Eye bleeds and peritoneal lavages were obtained at
24 or 48 h after injection. Lavage was recovered by i.p. injection
of cold PBS containing 5 mM EDTA and 1% BSA and by gently massaging
the abdomen of the animal. Samples were processed for flow cytometry as
described.
Proliferation assays
Spleens from different chimeric mice were dissected under sterile conditions. Mononuclear cells were obtained by density gradient centrifugation on Lympholite (Cedarlane Laboratories, Hornby, Ontario, Canada). Cells were resuspended in complete medium (RPMI plus 10% FBS). Cells (5 x 105/well) were dispensed in 96-well U-bottom plates, and the various stimuli were added (anti-CD3 from PharMingen (San Diego, CA); PMA, ionomycin, LPS, and Con A from Sigma (St. Louis, MO)). For mixed lymphocyte reaction, allogeneic irradiated splenocytes from BALB/c mice were used as targets at different ratios. Proliferation was quantitated by adding Alamar Blue for 24 h before reading the plates at 570 nm (26).
Statistical analysis
Data were analyzed and compared for statistically significant differences using Student’s t test.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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5, V, and
4 integrins during lymphoid and myeloid development
The role of 5 and V
integrins during lymphoid and myeloid development was investigated by
flow cytometric analysis of chimeric mice. CD3-positive T lymphocytes
are present in blood from 5- and
V-null/RAG-2 chimeric mice in percentages
similar to those in controls (Fig. 1
A). Moreover, no significant
differences were observed in the subsets of T cells
(CD4-CD8-,
CD4+CD8+,
CD4+CD8-, and
CD4-CD8+) present in the
thymus of 5 and V
chimeric mice compared with those in controls. Percentages of T
cells in V chimeric mice were also similar
to control values (not shown). In contrast, although there are T
lymphocytes in the blood of 4-null/RAG-2
chimeric mice (Fig. 1A), a severe defect occurs in T cell
differentiation within the thymus in the absence of
4 integrins as previously described for
chimeras on other backgrounds (17). In fact, histological
analysis of the thymus in 5 and
V chimeric mice shows cortical and medullary
areas similar to those in controls, whereas in
4 chimeric mice the thymus appears atrophic a
few weeks after birth (Fig. 1C).
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5- or
V-null/RAG-2 chimeric mice compared with
controls (Fig. 1
B). However, very few B cells were found in
the periphery, and almost none were found in the bone marrow of
4-null/RAG-2 chimeras (Fig. 1B) in
accord with previous findings in other backgrounds (17, 27). Histology of the spleen revealed a normal structure, with
lymphoid follicles and germinal centers, in 5
and V chimeras (Fig. 1C). However,
very few scattered lymphoid follicles, with poor germinal centers and
an increased ratio of red (erythromyeloid) to white (lymphoid) pulp,
were observed in 4 chimeric mice (Fig. 1C).
Myeloid development was also analyzed by flow cytometric staining with
specific markers for monocyte (Mac-1) and granulocyte (Gr-1)
populations. Although the percent chimerism was low because of the
presence of host-derived leukocytes, the data showed no significant
differences in numbers of Mac-1/Ly5.2+ or
Gr-1/Ly5.2+ cells in blood or bone marrow from
5- and V-null/RAG-2
chimeric mice compared with control values (Fig. 2). In contrast, the analysis of
4-null/RAG-2 chimeric mice showed that
monocytes, granulocytes, and their progenitors were present in blood
and bone marrow, respectively, but the numbers were significantly lower
than control values (Fig. 2) (27). Similar results for all
lineages were obtained when chimeras on a C57BL background were
analyzed (not shown).
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5,
V, and 4 integrins all recognize
fibronectin, their requirements during leukocyte development seem to be
different, suggesting incomplete redundancy in vivo. Thus, the major
conclusion from these data is that 4 integrins
are essential for leukocyte development, but 5
and V integrins are not. This might be due to
the nature of the site recognized on fibronectin by 4
integrins that is arginine-glycine-aspartic acid independent and
alternatively spliced, in contrast to that recognized by
5 and V integrins.
The specific recognition by 4 integrins of
other ligands, such as VCAM-1 and MAdCAM-1, might also play a role.
4-null/RAG-2 chimeric mice have a severe
defect in lymphocyte and myeloid development, as has previously been
shown in other backgrounds (17, 27). Regarding the ligands
involved in these defects, because VCAM-1-null mice do not show any
defect in leukocyte development (28), it seems more likely
that an as yet unknown ligand or the CS-1/V region of fibronectin plays
the essential role. In this regard, fibronectin has been shown to
affect the proliferation state of hemopoietic progenitors
through its recognition by 4 integrins
(29, 30). In fact, further analysis has shown that the
defects observed in the absence of
4 integrins are multilineage and probably due
to defects in the proliferation of hemopoietic progenitors
(27).
In contrast, it is still not possible to rule out the possibility that
5 or V integrins
participate in leukocyte development. In this regard,
5 integrin has previously been suggested to
play a role in transmigration of lymphoid progenitors
(31). Because 5 and
V recognize the same site on fibronectin,
although probably with different avidity depending on the cell type,
there might be substitution between these two receptors in their
putative roles during leukocyte development, as has been shown for
other in vivo and in vitro functions (32). Analysis of
inducible tissue-specific knockout mice will provide a more definitive
answer. Moreover, the participation of wild-type cells in the chimeric
system by, for instance, secreting soluble factors such as cytokines
cannot be completely ruled out.
Specific roles for 4 integrins in lymphocyte homing
in vivo
Because lymphocytes can develop without 5
or V integrins, and T lymphocytes and a few B
lymphocytes are present in the periphery of
4-null chimeric mice, we next wanted to
investigate the roles of these adhesion receptors in lymphocyte homing.
Migration to lymph nodes and mucosal sites was first analyzed by flow
cytometric staining. Similar percentages of T and B lymphocytes were
found in mesenteric nodes and Peyer’s patches of
5- and V-null/RAG-2
chimeric mice compared with controls (Fig. 3A).
4-deficient T and B lymphocytes were present
in mesenteric and inguinal nodes in similar percentages as in blood,
suggesting no defect in migration to peripheral lymph nodes (Fig. 3A) (17). However, no Peyer’s patches were
observed macroscopically in 4-null/RAG-2
chimeric mice, indicating a severe defect in trafficking of lymphocytes
to mucosal lymphoid sites (Fig. 3A). Histological analysis
of mesenteric nodes revealed a normal structure, with lymphoid
follicles and germinal centers, in 5 and
V chimeric mice (Fig. 3B). Although
lymphoid follicles were present in 4 chimeric
mice, they were smaller and lacked germinal centers, in concordance
with the defect observed in B cell development (Fig. 3B).
Histological sections of gut showed the presence of lymphoid cells
constituting Peyer’s patches in 5,
V, and control chimeric mice (Fig. 3B). In 4 chimeric mice, however,
only empty patches were found, with very few or no lymphocytes within
(Fig. 3B), confirming the severe defect in migration to
these sites in the absence of 4 integrins.
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5-, V-, and
4-null/RAG-2 chimeric mice (Fig. 3C). Almost no CD3+ lymphocytes were
present in RAG-2-deficient mice. No significant differences were
observed in the numbers of lymphocytes in either compartment compared
with those in wild-type controls (Fig. 3C). FACS analysis
showed a severe reduction in expression of ß7
on 4- null lymphocytes (Ly
9.1+; data not shown) reflecting the loss of
4ß7. However, a
minority population of
4-ß7+
Ly 9.1+ lymphocytes was observed in the chimeras.
These presumably represent an
4-ß7+
population that accounts for the efficient recruitment of T cells to
the intraepithelial and lamina propria compartments
(15).
The roles of 5 and V
integrins in lymphocyte trafficking in vivo have not previously
been reported. Herein, we show that lymphocytes can migrate
properly to different locations in the absence of
5 or V integrins.
This means that 5 and
V integrins are not essential for lymphocyte
migration to lymphoid organs or that they are able to substitute for
each other in this function, as discussed for leukocyte development.
Interestingly, 4 is essential for migration of
lymphocytes to Peyer’s patches. The 4
integrin chain can associate with ß1 or
ß7 subunits. The analysis of
ß7 knockout mice has shown a critical role for
ß7 receptors in migration of lymphocytes to
Peyer’s patches and an important role in trafficking to the intestinal
intraepithelial compartment and LP (16). The defect
observed in migration to Peyer’s patches in the absence of
4ß7 fits with the
presence of its specific ligand, MAdCAM-1, at this site. Previous
analysis of 4-deficient chimeric mice had
shown an essential role for these receptors in migration to Peyer’s
patches (17); however, conclusive data about their roles
in lymphocyte migration to intestinal epithelium and LP were missing.
Our current results demonstrate that 4
integrins are not critical for migration to these gut compartments,
suggesting that other ß7 partners might be
responsible for the defects. In this regard,
E-null mice show decreased numbers of IEL and
LPL (15). It is possible to conclude from these studies
that 4ß7 integrin is
essential for migration of lymphocytes to Peyer’s patches and that
Eß7 is critical for
localization of lymphocytes within the intestinal epithelium and LP.
Finally, it has been shown that ß2 integrins
interacting with ICAM-1 can also participate in the establishment of
the intestinal lymphocyte compartment (10).
Migration of 4-deficient lymphocytes is impaired
during thioglycolate-induced peritonitis
Because the 4 integrin ligand, VCAM-1, is
up-regulated on endothelium during inflammatory responses, migration of
4-deficient T lymphocytes was also
investigated in an inflammatory model, thioglycolate-induced
peritonitis. As shown in Fig. 4, the
relative percentages of
CD4+/Ly9.1+ T lymphocytes
present in the peritoneal lavage and blood of control/C57BL chimeras at
24 and 48 h are similar, showing no defects in migration (blood at
24 h, 23%; peritoneal lavage at 24 h, 28%; blood at 48
h, 30%; peritoneal lavage at 48 h, 34%; n = 3).
However, the relative percentages of T lymphocytes in the peritoneal
lavage of 4 chimeric mice were significantly
lower compared with their relative percentages in blood (Fig. 4; blood
at 24 h, 20.5%; peritoneal lavage at 24 h, 8.3%; blood at
48 h, 21%; peritoneal lavage at 48 h, 7.8%;
n = 3), indicating an impairment of T lymphocyte
migration to inflammatory foci in the absence of
4 integrins. This defect is most likely due to
the lack of interaction of 4-null lymphocytes
with VCAM-1 at the inflammatory foci. However, because T lymphocytes in
4-chimeric mice are developed in the thymus
only at very early stages of development, it is conceivable that they
could also lack some switch necessary to home properly to these sites,
as reported for other homing pathways (33).
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4 integrins might have during
inflammatory processes had been investigated previously using Abs
against 4 integrins or specific inhibitory
peptides (for review, see Ref. 19). These studies have
shown a role for 4 integrins during allergic
asthma, delayed contact hypersensitivity, experimental allergic
encephalomyelitis, rheumatoid arthritis, and chronic inflammatory bowel
disease. In this report we show that 4
integrins are required in vivo for the efficient migration of
lymphocytes to an inflammatory focus. These data reinforce the
therapeutic approaches that are under clinical trial using
4 inhibitors for the treatment of different
chronic inflammatory diseases. However, it is also important to
emphasize that the complete blockade of 4
integrin function might have deleterious effects on the development of
the different blood lineages and on the homing of lymphocytes to
Peyer’s patches in humans as has been demonstrated for mice (Refs.
17 and 27 and this report).
Lymphocyte proliferation and activation occur in the absence of
5, V, or 4 integrins
Lymphocyte activation was also studied in the absence of these
integrin receptors. First, it is interesting to note that
5-, V-, and
4-null/RAG-2 chimeric mice do not show any
obvious increases in infectious or inflammatory diseases compared with
control chimeras during their life span (up to 2 yr) in contrast to
RAG-2-deficient mice, which get sick after 6 mo in the same
environment, suggesting an appropriate function of the immune system.
To assess integrin function during lymphocyte activation, in vitro
approaches were undertaken using integrin-deficient lymphocytes.
Splenocytes from 5-,
V-, or 4-null/RAG-2
chimeric mice were used for in vitro proliferation assays in the
presence of serum containing fibronectin. As shown in Fig. 5A, no major differences in
the proliferation of T lymphocytes induced by Con A or anti-CD3
were observed in the absence of 5-,
V-, or 4-integrins
compared with that of cells from control chimeric mice. Similar results
were obtained when LPS was used to stimulate proliferation of B
lymphocytes (Fig. 5A). Intercellular adhesion-mediated
activation was analyzed by mixed lymphocyte reaction in the presence of
serum. Splenocytes deficient for 5-,
V-, or 4-integrins
were cocultured in the presence of different ratios of irradiated
allogeneic splenocytes. As shown in Fig. 5B, no major
differences were observed in lymphocyte proliferation in the absence of
integrin receptors compared with controls. The role of integrins in the
activation of lymphocytes was also investigated by checking their
activation state by flow cytometry. The expression of the lymphoid
activation markers CD25 (IL-2R) and CD69 was up-regulated on
splenocytes deficient for 5-,
V-, or 4-integrin
receptors similarly to that in controls on day 3 after stimulation with
PMA and ionomycin (Fig. 5C). Relative secretion of IgM by
5-, V-, or
4-deficient splenocytes upon LPS stimulation
was also similar to that in controls as assessed by ELISA (data not
shown). Together, these data indicate that lymphocytes can proliferate
and be activated properly in the absence of 5,
V, or 4
integrins.
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5, V, or
4 integrins are not essential for in vitro
activation of lymphocytes. However, synergism of these adhesion
receptors in coactivating lymphocytes under certain conditions in vivo
could still be possible. Moreover, because accessory pathways seem to
be multiple, it is not possible to rule out substitution by other
accessory molecules. Given the lethality of all three integrin
mutations, further analyses in vivo are challenging. Inducible
tissue-specific knockout mice will give further clues about the
functions of these receptors during the immune response in
vivo.
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Acknowledgments |
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Footnotes |
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2 Current address: Immunology Department, Hospital de la Princesa, Universidad Autónoma de Madrid, 28006 Madrid, Spain.
3 Current address: Department of Protein Chemistry, Max Planck Institute for Biochemistry, D-82152 Martinsried, Germany.
4 Address correspondence and reprint requests to Dr. Richard O. Hynes, Howard Hughes Medical Institute, Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
5 R.O.H. is an investigator with the Howard Hughes Medical Institute.
6 Abbreviations used in this paper: MAdCAM-1, mucosal addressin cell adhesion molecule-1; LP, lamina propria: IEL, intraepithelial lymphocyte; RAG-2, recombinase-activating gene 2.
Received for publication May 2, 2000. Accepted for publication July 27, 2000.
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References |
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4- and ß7-integrins in hematopoiesis, lymphocyte trafficking and organ development. Curr. Top. Microbiol. Immunol. 231:23.[Medline]
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4ß7 on a subset of human CD4+ memory T cells with hallmarks of gut tropism. J. Immunol. 151:717.[Abstract]
4ß7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74:185.[Medline]
E (CD103)-deficient mice. J. Immunol. 162:6641.4 integrins during fetal and adult hematopoiesis. Cell 85:997.[Medline]
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5 integrin. J. Cell Biol. 143:849.V integrins. Cell 95:507.[Medline]
4 integrins regulate the proliferation/differentiation balance of multilineage hematopoietic progenitors in vivo. Immunity 11:555.[Medline]
4ß1-integrin binding sequences of fibronectin on growth of cells from human hematopoietic progenitors. Blood 91:3230.5ß1 integrin can be replaced by V integrins. Mol. Biol. Cell 7:1737.[Abstract]
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 N. J. Sullivan, M. Peterson, Z.-y. Yang, W.-p. Kong, H. Duckers, E. Nabel, and G. J. Nabel Ebola Virus Glycoprotein Toxicity Is Mediated by a Dynamin-Dependent Protein-Trafficking Pathway J. Virol., January 1, 2005; 79(1): 547 - 553. [Abstract] [Full Text] [PDF]
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S. J. Hyduk, J. Oh, H. Xiao, M. Chen, and M. I. Cybulsky Paxillin selectively associates with constitutive and chemoattractant-induced high-affinity {alpha}4{beta}1 integrins: implications for integrin signaling Blood, November 1, 2004; 104(9): 2818 - 2824. [Abstract] [Full Text] [PDF]
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 M. J. Calzada, L. Zhou, J. M. Sipes, J. Zhang, H. C. Krutzsch, M. L. Iruela-Arispe, D. S. Annis, D. F. Mosher, and D. D. Roberts {alpha}4{beta}1 Integrin Mediates Selective Endothelial Cell Responses to Thrombospondins 1 and 2 In Vitro and Modulates Angiogenesis In Vivo Circ. Res., March 5, 2004; 94(4): 462 - 470. [Abstract] [Full Text] [PDF]
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 L. M. Scott, G. V. Priestley, and T. Papayannopoulou Deletion of {alpha}4 Integrins from Adult Hematopoietic Cells Reveals Roles in Homeostasis, Regeneration, and Homing Mol. Cell. Biol., December 15, 2003; 23(24): 9349 - 9360. [Abstract] [Full Text] [PDF]
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B. Adkins Peripheral CD4+ Lymphocytes Derived from Fetal versus Adult Thymic Precursors Differ Phenotypically and Functionally J. Immunol., November 15, 2003; 171(10): 5157 - 5164. [Abstract] [Full Text] [PDF]
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Y. Katayama, A. Hidalgo, B. C. Furie, D. Vestweber, B. Furie, and P. S. Frenette PSGL-1 participates in E-selectin-mediated progenitor homing to bone marrow: evidence for cooperation between E-selectin ligands and {alpha}4 integrin Blood, September 15, 2003; 102(6): 2060 - 2067. [Abstract] [Full Text] [PDF]
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R. F. de Pooter, S. K. Cho, J. R. Carlyle, and J. C. Zuniga-Pflucker In vitro generation of T lymphocytes from embryonic stem cell-derived prehematopoietic progenitors Blood, September 1, 2003; 102(5): 1649 - 1653. [Abstract] [Full Text] [PDF]
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Y.-C. Gu, J. Kortesmaa, K. Tryggvason, J. Persson, P. Ekblom, S.-E. Jacobsen, and M. Ekblom Laminin isoform-specific promotion of adhesion and migration of human bone marrow progenitor cells Blood, February 1, 2003; 101(3): 877 - 885. [Abstract] [Full Text] [PDF]
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 Z. Li, M. J. Calzada, J. M. Sipes, J. A. Cashel, H. C. Krutzsch, D. S. Annis, D. F. Mosher, and D. D. Roberts Interactions of thrombospondins with {alpha}4{beta}1 integrin and CD47 differentially modulate T cell behavior J. Cell Biol., April 29, 2002; 157(3): 509 - 519. [Abstract] [Full Text] [PDF]
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T. Papayannopoulou, G. V. Priestley, B. Nakamoto, V. Zafiropoulos, and L. M. Scott Molecular pathways in bone marrow homing: dominant role of {alpha}4{beta}1 over {beta}2-integrins and selectins Blood, October 15, 2001; 98(8): 2403 - 2411. [Abstract] [Full Text] [PDF]
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J.-P. Levesque, Y. Takamatsu, S. K. Nilsson, D. N. Haylock, and P. J. Simmons Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor Blood, September 1, 2001; 98(5): 1289 - 1297. [Abstract] [Full Text] [PDF]
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D. Bouvard, C. Brakebusch, E. Gustafsson, A. Aszodi, T. Bengtsson, A. Berna, and R. Fassler Functional Consequences of Integrin Gene Mutations in Mice Circ. Res., July 30, 2001; 89(3): 211 - 223. [Abstract] [Full Text] [PDF]
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U. G. Strauch, R. C. Mueller, X. Y. Li, M. Cernadas, J. M. G. Higgins, D. G. Binion, and C. M. Parker Integrin {{alpha}}E(CD103){{beta}}7 Mediates Adhesion to Intestinal Microvascular Endothelial Cell Lines Via an E-Cadherin-Independent Interaction J. Immunol., March 1, 2001; 166(5): 3506 - 3514. [Abstract] [Full Text] [PDF]
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Z. Li, M. J. Calzada, J. M. Sipes, J. A. Cashel, H. C. Krutzsch, D. S. Annis, D. F. Mosher, and D. D. Roberts Interactions of thrombospondins with {alpha}4{beta}1 integrin and CD47 differentially modulate T cell behavior J. Cell Biol., April 29, 2002; 157(3): 509 - 519. [Abstract] [Full Text] [PDF]
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