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*
Department of Immunology, Medical Clinic, University Hospital Eppendorf, Hamburg, Germany;
Institute of Cell Biology, University of Münster, Münster, Germany;
Heinrich Pette Institute, Hamburg, Germany; and
§
Institute for Experimental Medicine, University of Erlangen-Nürnberg, Erlangen, Germany
A. Hamann, F. Austrup, W. Tietz, and D. Jablonski-Westrich. Activation induces rapid and profound alterations in the trafficking of T cells. Submitted for publication.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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L-selectin is expressed on leukocytes; on naive T cells, it is crucial for recirculation through high endothelial venules (4), while murine CD4+ memory cells, which are L-selectinlow, enter lymph nodes only at low rates (5). In contrast, both E-selectin and P-selectin are expressed on endothelial cells and become up-regulated during inflammation. P-selectin was initially found on activated platelets; its expression on the surface of endothelial cells is induced within a few minutes by appropriate stimuli (6, 7).
A ligand for P-selectin, the P-selectin glycoprotein ligand-1 (PSGL-1),4 was first identified on human and murine myeloid cells (8, 9, 10). It has since been shown that subsets of T cells, notably activated or effector cells, can also bind to P-selectin and express functional PSGL-1 (3, 11, 12, 13, 14). Both PSGL-1 and ESL-1 (E-selectin ligand-1), the major ligands for E-selectin on murine cells (15), are constitutively expressed on T cells, but gain a role as selectin ligands only after appropriate posttranslational modification, presumably glycosylation (14) (see Note added in proof).
A ligand for E-selectin on human lymphocytes was identified as an antigenic determinant selectively expressed by the majority of T cells in skin but by only a minor subset of memory/effector cells in the blood (16, 17). Accordingly, the epitope was called the cutaneous lymphocyte-associated antigen (CLA). Recently, it has been shown that the CLA epitope is an E-selectin-binding modification of the protein core of PSGL-1 (18). The striking association between expression and localization of the cells led to the assumption that E-selectin is involved in targeting the CLA+ subpopulation into skin. However, experimental proof for the role of E- as well as P-selectin in the recruitment of T cells into the (inflamed) skin was largely lacking until the generation of E- and P-selectin-deficient mice. Studies in P-selectin-deficient mice showed a significant reduction of CD4+ T cells accumulation into the skin in oxazolone-induced delayed-type contact hypersensitivity (DTH) (19). In contrast to the rather mild phenotypes observed in mice deficient in a single selectin gene (20), those thay were doubly deficient showed a virtual absence of leukocyte rolling and low extravasation at sites of inflammation (21). Whether migration into the normal skin is also affected was not reported. These data supported the hypothesis that E-selectin and P-selectin are functionally redundant in the mouse (19, 20, 21).
The relationship between expression of P-selectin and E-selectin ligands on T cells in vivo, their kinetics during an immune reaction, and their precise functional role have not yet been analyzed. We have recently shown that in vitro-generated Th1-type cells can express ligands for both P- and E-selectin and are recruited into the inflamed skin, but also into the inflamed synovium, by use of both selectins (13). In this study we analyze the development and characteristics of in vivo occurring CD4+ T cells, which express ligands for endothelial selectins. The data indicate that ligands for both P- and E-selectin become transiently expressed on a subset of CD4+ cells in murine lymph nodes after antigenic stimulation. These cells predominantly display an activated phenotype. FACS isolation and reinjection of these cells and the use of blocking Abs provide evidence that both selectins are involved in the entry of CD4+ cells into acutely inflamed sites in the skin.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Anti-CD8 (53-6.72 (22)) and anti-Mac-1 (M1/70 (23)) were
obtained from the American Type Culture Collection (Manassas, VA).
Anti-L-selectin (MEL-14 (4)) was kindly provided by E. C. Butcher
(Stanford University, Stanford, CA). The E-selectin-specific mAb UZ4
(24) and the P-selectin-specific mAb RB40.34 (25) were prepared as
described. mAbs were purified by affinity chromatography as described
(26) or precipitated by ammonium sulfate from serum-free supernatants.
Phycoerythrin (PE)- or FITC-labeled anti-human IgG,
anti-CD45RB, clone 23G2, anti-IFN-
, clone R46A2,
anti-IL-4, clone 11B11, anti-IL-2R, anti-CD71, and
anti-
4ß7, clone DATK32 were obtained from
PharMingen (Hamburg, Germany). Biotin-conjugated anti-CD4 and
PE-labeled goat anti-rat Ig (mouse absorbed) were obtained from
Medac (Hamburg, Germany); rabbit anti-rat IgG was from Dako
(Hamburg, Germany), and PerCP-conjugated streptavidin was from Becton
Dickinson (Heidelberg, Germany). The E- and P-selectin-IgG fusion
proteins were produced as described (27).
Animals and induction of skin inflammation
Female BALB/c mice, 8 to 16 wk of age, obtained from Harlan-Winkelmann (Borchen, Germany), were used. A cutaneous DTH reaction was induced by skin painting with 0.5% 2,4-dinitrofluorobenzene (DNFB) in aceton-olive oil (4:1) on day -21 and -20 and rechallenged with 0.5% DNFB on day -4 for isolation of P- and E-selectin-binding cells, if not otherwise stated, or on day -1 for homing experiments.
Cells
Lymphocytes from s.c. draining lymph nodes and other organs were prepared by teasing from skin-sensitized and rechallenged or control mice. Lymphocytes from peripheral blood or spleen were isolated by density centrifugation as described (5). Dead cells were removed by centrifugation on 17.0% isotonic Nycodenz (Nyegaard, Oslo, Norway), and the cells were washed twice with PBS. For the isolation of CD4+ T cells, they were incubated at 4°C with an Ab mixture containing anti-CD8 and anti-MAC-1. After incubation, cells were washed and depleted from non-T cells by two subsequent panning steps on petri dishes coated with rabbit anti-rat Ig (100 µg/ml, cross-reacting with mouse IgG) at 4°C. The average purity of the CD4+ cells after panning was >95% as determined by FACS analysis.
Immunofluorescence staining and FACS sorting
For the phenotypical characterization of the CD4+ E- or P-selectin-binding cells, we used a FACScan or FACSCalibur flow cytometer (Becton Dickinson). The cells were labeled with soluble E- or P-selectin chimera containing the Fc part of human IgG at 0.4 to 10 µg/ml in HBSS with Ca2+/Mg2+ for 15 min, biotin-conjugated anti-CD4 mAb, and FITC-conjugated mAbs against various other cell surface markers. Bound selectin constructs were detected with PE- or FITC-labeled anti-human IgG (20 µg/ml), CD4 with PerCP-conjugated streptavidin. Straining was done strictly at 4°C. Cells were analyzed by FACS after fixation with 1% paraformaldehyde. For negative controls, a human CEA-Ig chimeric construct and isotype control mAbs were applied; the myeloid cell line 32Dcl3 served as a positive control for selectin-ligand expression.
For the sorting of E- or P-selectin-binding T cell subsets, isolated CD4+ T cells were labeled with E- or P-selectin as described above and subsequently sorted into positive and negative fractions on a FACS, M.Fl. cell sorter (Cytomation BioInstruments, Ft. Collins, CO).
The isolated populations were >95% pure with respect to CD4 and selectin ligand expression upon reanalysis. To remove the selectin-IgG chimera from the cells, the sorted fractions were treated for 20 min with 5 mM EDTA. Control experiments showed no effect of cell sorting or EDTA treatment on the migration behavior of total lymph node cells.
For FACS analysis of cytokine production, CD4+ T cells were
isolated and stimulated with PMA (50 ng/ml) and ionomycin (500 ng/ml)
for 3 h and, after addition of brefeldin A (10 µg/ml), for a
further 2 h. The cells were labeled with selectin ligands, fixed,
permeabilized, and stained with PE-conjugated anti-cytokine mAbs
for either Il-4 or IFN- production as described (28) and
FITC-labeled anti-human Ig for selectin binding. Alternatively,
CD4+ cells were triple labeled for selectin binding and
intracellular Il-4 and IFN- after the PMA/ionomycin stimulation.
Control experiments had shown that the stimulation did not
significantly alter the expression of the selectin ligands. As a
negative control for intracellular cytokine staining, cells were either
incubated with a PE-conjugated isotype controls, unlabeled
anti-cytokine mAb, or labeled in the presence of an excess of soluble
cytokines.
In vivo homing assays
The migration of radioactively labeled lymphocytes was analyzed as described (29, 30). In short, cells were labeled with 20 µCi/ml (750 kBq/ml) sodium [51Cr]chromate for 1 h at 37°C. Blasts were selectively labeled by incorporation of [125I]iododeoxyuridine (1 µCi (37 kBq)/ml) for 2 h. Dead cells were removed by centrifugation on a Nycodenz density cushion. Cells (0.5–2 x 106) resuspended in 0.3 ml PBS were injected with or without added Ab (200 µg mAb per mouse) into the tail vein. Mice were killed 1 or 24 h later, and the distribution of the radioactivity in skin pieces of 2.5 cm2 in size, as well as in various other organs and in the remaining body, was measured. Blood values were computed for a 2-ml volume. Extended counting times and multiple background measurements were used allowing a statistical error below 10% for samples containing down to 0.1% of radioactivity recovered within the animals. The significance of differences between the means were analyzed with Student’s t test. A variety of isotype control mAbs, e.g., nonblocking anti-VCAM-1 IgM mAb (4EE6) and and nonblocking anti-HEV IgG1 mAb (Meca 325) were used, among others, and tested in inflamed or noninflamed tissues with no significant differences compared with controls that did not receive Abs.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The expression of ligands for the endothelial selectins was studied on freshly isolated CD4+ cells from s.c. lymph nodes by testing their ability to bind soluble E-selectin- or P-selectin-Ig chimera.
In untreated mice, the number of E-selectin-binding CD4+ T
cells was very low, amounting to only 0.5 to 1.5% of total
CD4+ cells in the cutaneous lymph nodes. The percentage of
P-selectin-binding T cells was slightly higher, in the range of 2 to
4% of total CD4+ T cells (Figs. 1
, a and b, and
3d). Similar numbers of these cells were found in the
spleen (not shown).
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, a–d).
Analysis of cells sorted from draining lymph nodes in skin-sensitized
animals showed that all isolated E-selectin-binding CD4+ T
cells also expressed P-selectin ligands, whereas 70% of the
P-selectin-binding CD4+ T cells also bound E-selectin (Fig. 1, e and f).
Figure 2 shows the kinetics of E-selectin
ligand expression of two separate experiments and P-selectin ligand
expression. The percentage of the E-selectin-binding T cells increased
to 4% on day 4 after the second priming; the percentage of the
P-selectin-binding CD4+ T cells increased to 10%. After
challenge, the percentage of E-selectin-binding CD4+ T
cells increased to 6 to 9% and that of the P-selectin-binding
CD4+ T cells to 14% (Fig. 1, c and
d). Similar ranges were found after challenge in
repeated experiments. At late time points after antigenic stimulation,
the levels of selectin-binding cells had dropped to values approaching
those of unchallenged mice. Older mice without stimulation contained
levels of selectin-binding CD4+ cells in the same range as
young mice (data not shown).
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E- and P-selectin-binding T cells predominantly display the phenotype of activated cells
To analyze this question further, the phenotypic profile of CD4+ cells expressing ligands for E- and P-selectin was determined, especially with respect to their activation and differentiation stage.
Figure 3a shows the expression
of several activation/differentiation markers on the E- or
P-selectin-binding CD4+ T cells isolated from draining
lymph nodes at day 4 after rechallenge. In these stimulated lymph
nodes, a significant fraction of the total CD4+ cells is in
an activated stage. Among P- and E-selectin-binding cells, the
percentage of activated cells is much higher: roughly 75% of the
E-selectin-binding CD4+ T cells were found to carry the
IL-2R and expressed the transferrin receptor (CD71, not shown). The
percentage of P-selectin-binding CD4+ T cells that express
activation markers was found to be slightly lower, with between 50 and
70% carrying the above markers. Similar ranges were found in repeated
experiments. Half of both populations also expressed the early
activation marker CD69 (data not shown). It has not yet been possible
to determine whether these activation markers are expressed, for the
most part, on the same subfraction of cells or whether they delineate
only partially overlapping subsets.
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c).
In the human, the expression of CLA, a ligand for E-selectin, has been
shown to be inversely correlated with expression of the mucosal homing
receptor 4ß7. We did not observe this
correlation in the mouse (Fig. 3). Selectin-binding cells were also
observed in other organs such as Peyer’s patches, spleen, or
peripheral blood (Fig. 3b), and also in contralateral
lymph nodes (not shown), albeit in lower numbers (corresponding to the
lower numbers of activated cells found in these compartments after
stimulation via a skin site). High numbers of selectin-binding cells
were also found in the lamina propria and other noncutaneous sites in a
model of intestinal inflammation (33).
E- and P-selectin-binding T cells isolated from untreated mice (Fig. 3d) or from mice several weeks after a sensitization
cycle (Fig. 3e) displayed a similar, largely
activated phenotype. Also, in this setting, no evidence was found that
the selectin-binding cells were enriched in the subset of memory
cells.
In conclusion, CD4+ cells expressing ligands for endothelial selectins are found in increased numbers only in stimulated mice. This cell population is heterogeneous with respect to activation markers, with a bias for activated cell stages. In the smaller subset expressing ligands for E-selectin, the activation is more pronounced.
A large percentage of selectin-binding CD4+ cells are cytokine-producing effector cells
Previously, we have shown that in vitro-generated Th1 cells, but
not Th2 cells, express ligands especially for P-selectin (13, 14). It
was therefore of interest to determine whether the expression of
selectin ligands on cells differentiated in vivo correlates with an
effector cell stage characterized by the production of distinct
cytokines. Figure 4 shows that slightly
more than half of the IFN--producing Th1 cells are found in the
P-selectin binding fraction, and high producers are enriched in this
fraction (mean fluorescence in the IFN- channel: 1.8 x that of
the P-selectin-negative cells). In the DTH model used, very few
IL-4-producing Th2 cells are found in the draining lymph nodes; among
these, however, both selectin-binding and non-binding cells were found.
Ligands for E-selectin are expressed only on a smaller percentage of
cytokine-producing Th1 cells. In conclusion, approximately half of the
cytokine producers express ligands for P-selectin, while less of them
express ligands for E-selectin; thus, activated effector cells are
enriched in the selectin-binding fraction of CD4+
cells. The close association between cytokine phenotype and expression
of selectin ligands is, however, not found in this model of in vivo
activation of T cells.
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The use of soluble selectin-Ig chimeras that bind reversibly, in a Ca2+-dependent manner, to their ligands allowed us to isolate CD4+ subsets expressing the functional ligands in a native state, to analyze their migratory properties in vivo.
CD4+ T cells were labeled with the E- or
P-selectin-Ig construct and a secondary Ab, then sorted in positive and
negative fractions on a FACS. The resulting populations of the E- or
P-selectin-binding fraction were 95% positive (Fig. 5, c and d).
The negative fraction contained 1% or less of selectin-binding cells
(Fig. 5, a and b). After removal of the
selectin-Ab complexes by washing in EDTA, cells were labeled with
sodium [51Cr]chromate and
[125I]iododeoxyuridine and injected i.v. Control
experiments showed that neither cell sorting nor EDTA treatment had an
effect on the migration behavior of lymph node cells (data not
shown).
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a, the
E-selectin-binding CD4+ T cells entered the inflamed skin
to a much higher extent within the first hour after i.v. injection,
compared with the total fraction of negative cells or to
[125I]iododeoxyuridine-labeled blasts present in the
negative fraction. CD4+ cells of memory phenotype, not
enriched for selectin-binding subsets, also lack a significant capacity
to enter the inflamed skin (34). Similar results were obtained with
P-selectin-binding CD4+ T cells (Fig. 7a). Twenty-four hours
after injection, the percentage of E-selectin-binding cells
within the inflamed skin has increased further (Fig. 6c).
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As shown in Figure 6b, the migration of the
E-selectin-binding CD4+ T cells into mesenteric lymph nodes
and spleen was strongly reduced and a high localization within the lung
was observed. Similar results were obtained for the P-selectin-binding
CD4+ T cells (Fig. 7b). With this
population, a slightly increased accumulation in the liver was observed
in several experiments. These trafficking preferences contrast to that
of resting CD4+ cells and correspond, for the most part, to
that of those CD4+ blasts not expressing selectin ligands.
Indeed, a reduced migration into lymphoid tissues and a high affinity
to lung and liver is characteristic of activated lymphocytes in general
(35).5 It is not due to selectin-mediated
interactions, as Abs against E- and P-selectin were without effect on
the distribution of the selectin-binding cells among noninflamed
tissues (data not shown).
Both E- and P-selectin are involved in the recruitment of T cells into the inflamed skin
The exclusive capacity of CD4+ cells expressing ligands for endothelial selectins to migrate into inflamed skin strongly suggests, but does not prove, a crucial role of these epitopes for homing into the inflamed skin. The capacity of isolated E- or P-selectin-binding CD4+ T cells to migrate into sites of cutaneous inflammation was tested, therefore, in the presence of mAbs blocking either E-selectin or P-selectin.
Figure 8 shows that the migration of
E-selectin- and P-selectin-binding CD4+ T cells depends on
both selectins. E-selectin- or P-selectin-binding CD4+ T
cells show a partial reduction in migration into the inflamed skin by
mAb against either E- or P-selectin. An additive effect was observed
when both Abs were combined, resulting in almost complete
inhibition.
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These results clearly show that the two selectins together play a crucial role in migration into inflamed skin, but their function largely overlaps under the conditions tested.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Indeed, the majority of E- and P-selectin-binding CD4+ T cells was found to express activation markers such as the Il-2R or CD71, although a distinct fraction of small, phenotypically naive/resting cells could also be distinguished among them. L-selectin and CD45RB, which are low on activated as well as on memory T cells (34), were less strongly associated with the selectin-binding cell subset. A slightly increased cell size. especially of the E-selectin binding cells, as indicated by the scatter values, would argue against these cells being true resting memory cells. This phenotype is compatible with the previous characterization of human T cells carrying the E-selectin-binding epitope CLA as cells in the activated-to-memory transition (16, 32), but suggests that, in mice, selectin ligands are expressed on activated rather than on memory cells. This conclusion is also supported by the merely transient occurrence of selectin-binding cell subsets after antigenic challenge.
Previously, we have shown that in vitro-generated Th1 cells, but not
Th2 cells, express the PSGL-1 protein in a modified form, rendering it
a functional P-selectin ligand (13, 14). These data suggested that
differentiation into distinct effector cell stages is linked with an
up-regulation of the synthesis of functional selectin ligands. In the
DTH model elicited by DNFB, almost exclusively, Th1 cells are induced
in vivo. In this model, roughly half of the IFN--producing Th1 cells
express P-selectin ligands, and this subset comprised especially the
high producers. However, the small number of Il-4-producing Th2 cells
found in the draining lymph nodes also showed selectin binding on part
of them. These data indicate that selectin-binding epitopes are
up-regulated on cytokine producers. It appears, however, that
CD4+ effector cells generated in the skin inflammation
model used here do not exhibit the close correlation between selectin
binding and cytokine subset found for in vitro-generated Th1/Th2
cells.
The CD4+ subset binding E-selectin was smaller than that binding P-selectin in all compartments studied. Double staining with E- vs P-selectin-Ig, to analyze the relationship between cells expressing the respective ligands, was not possible due to technical reasons. An analysis of sorted (either P- or E-selectin binding) cells indicated that the E-selectin-binding fraction is a subfraction of cells binding P-selectin. E-selectin-binding cells display a higher degree of activation compared with the total P-selectin-binding fraction. In addition, those cells that carry ligands for E-selectin were found to express especially high levels of P-selectin ligands. This was also found for cultured CD4+ effector cells (unpublished data; see also Note added in proof).
This study shows that both the E-selectin-binding CD4+ T cells and the P-selectin-binding CD4+ T cells efficiently migrate into the inflamed skin, compared with a poor homing into skin displayed by CD4+ cells lacking ligands for E- and P-selectin by ligand-negative CD4+ blasts and by the total memory cell fraction of peripheral lymph nodes from untreated mice.5 The expression of ligands for endothelial selectins suggests, therefore, a crucial role of these epitopes for homing into the inflamed skin.
The migration of selectin-binding cells into other, noninflamed tissues was found to be very similar to that of activated or memory CD4+ T cells, in which migration is characterized by a localization in nonlymphoid and a reduced recirculation through lymphoid tissues (5, 35); a specific influence of selectin ligands for trafficking through these organs could be identified neither with sorted cells nor in Ab inhibition experiments. Additional data indicate that the expression of selectin ligands enables CD4+ cells to migrate not only into the inflamed skin, but also into other inflamed tissues (Ref. 13; Y.A. and A.H., unpublished observations).
The present results do not support the view that expression of ligands for endothelial selectins predisposes T cells toward homing into normal, noninflamed skin.
The crucial role of ligands for E-and P-selectin for migration into the inflamed skin is confirmed by Ab inhibition experiments. Blocking of either E- or P-selectin reduced the migration of the E-selectin-binding CD4+ T cells into the inflamed skin by >50% and reduced that of P-selectin-binding CD4+ T cells somewhat less. Inhibition of both endothelial selectins together blocked completely the migration into the inflamed skin, indicating that E- and P-selectin can largely substitute for each other in recruiting cells into the inflamed skin. Similar findings were observed with in vitro-generated Th1-type cells (13, 14). Thus, the overlapping function of E- and P-selectin identified by studies on neutrophils (19, 20) also applies in its role in T cell recruitment into inflamed tissue.
In conclusion, E- and P-selectin-binding CD4+ T cells are a heterogeneous population of, predominantly, activated effector T cells with a high capacity to migrate into inflamed, but not normal skin. The two endothelial selectins together and their ligands are obligatory for a recruitment of the CD4+ cells into the inflamed site, and their function cannot be replaced by integrins or L-selectin.
Note added in proof. A recent study shows that fucosyltransferase-VII is a key element in
regulating the synthesis of P- as well as E-selectin ligands in
lymphocytes and demonstrates that the level of this enzyme determines
whether P-selectin ligands are expressed alone or in conjunction with
E-selectin ligands (Knibbs, R. N., R. A. Craig, P. Mály, P. L.
Smith, F. M. Wolber, N. E. Faulkner, J. B. Lowe, and L. M. Stoolman.
1998. -(1, 3)Fucosyltransferase-VII-dependent synthesis of P-selectin
ligands on cultured T lymphoblasts. J. Immunol. In press.)
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Acknowledgments |
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Footnotes |
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2 This report was submitted by W.T. in partial fulfillment of the requirements for a Ph.D. from the University of Hamburg.
3 Address correspondence and reprint requests to Prof. Dr. A. Hamann, Humboldtuniversität Berlin, Charité, Med. Klinik III/Dt. Rheumaforschungszentrum, Monbijoustr. 2a, 10117 Berlin, Germany. E-mail address:
4 Abbreviations used in this paper: PSGL-1, P-selectin glycoprotein ligand-1; CLA, cutaneous lymphocyte Ag; PE, phycoerythrin; DTH, delayed-type hypersensitivity; DNFB, 2,4-dinitrofluorobenzene.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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4-integrins in lymphocyte homing to mucosal tissues in vivo. J. Immunol. 152:3282.[Abstract]
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Y. H. Cai, A. Alvarez, P. Alcaide, P. Duramad, Y.-C. Lim, P. Jarolim, J. B. Lowe, F. W. Luscinskas, and A. H. Lichtman Abrogation of Functional Selectin-Ligand Expression Reduces Migration of Pathogenic CD8+ T Cells into Heart. J. Immunol., June 1, 2006; 176(11): 6568 - 6575. [Abstract] [Full Text] [PDF]
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T. Schreiber, S. Ehlers, S. Aly, A. Holscher, S. Hartmann, M. Lipp, J. B. Lowe, and C. Holscher Selectin Ligand-Independent Priming and Maintenance of T Cell Immunity during Airborne Tuberculosis J. Immunol., January 15, 2006; 176(2): 1131 - 1140. [Abstract] [Full Text] [PDF]
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P. R. Mangan, D. O'Quinn, L. Harrington, C. S. Bonder, P. Kubes, D. F. Kucik, D. C. Bullard, and C. T. Weaver Both Th1 and Th2 Cells Require P-Selectin Glycoprotein Ligand-1 for Optimal Rolling on Inflamed Endothelium Am. J. Pathol., December 1, 2005; 167(6): 1661 - 1675. [Abstract] [Full Text] [PDF]
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K. Siegmund, M. Feuerer, C. Siewert, S. Ghani, U. Haubold, A. Dankof, V. Krenn, M. P. Schon, A. Scheffold, J. B. Lowe, et al. Migration matters: regulatory T-cell compartmentalization determines suppressive activity in vivo Blood, November 1, 2005; 106(9): 3097 - 3104. [Abstract] [Full Text] [PDF]
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B. Johansson-Lindbom, M. Svensson, O. Pabst, C. Palmqvist, G. Marquez, R. Forster, and W. W. Agace Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing J. Exp. Med., October 17, 2005; 202(8): 1063 - 1073. [Abstract] [Full Text] [PDF]
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J. Yoo, M. Omori, D. Gyarmati, B. Zhou, T. Aye, A. Brewer, M. R. Comeau, D. J. Campbell, and S. F. Ziegler Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin J. Exp. Med., August 15, 2005; 202(4): 541 - 549. [Abstract] [Full Text] [PDF]
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 K. Viswanathan, C. Daugherty, and F. S. Dhabhar Stress as an endogenous adjuvant: augmentation of the immunization phase of cell-mediated immunity Int. Immunol., August 1, 2005; 17(8): 1059 - 1069. [Abstract] [Full Text] [PDF]
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D. A. Carlow, M. J. Williams, and H. J. Ziltener Inducing P-Selectin Ligand Formation in CD8 T Cells: IL-2 and IL-12 Are Active In Vitro but Not Required In Vivo J. Immunol., April 1, 2005; 174(7): 3959 - 3966. [Abstract] [Full Text] [PDF]
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J. R. Mora, G. Cheng, D. Picarella, M. Briskin, N. Buchanan, and U. H. von Andrian Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues J. Exp. Med., January 18, 2005; 201(2): 303 - 316. [Abstract] [Full Text] [PDF]
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C.-J. Chang, K.-F. Tai, S. Roffler, and L.-H. Hwang The Immunization Site of Cytokine-Secreting Tumor Cell Vaccines Influences the Trafficking of Tumor-Specific T Lymphocytes and Antitumor Efficacy against Regional Tumors J. Immunol., November 15, 2004; 173(10): 6025 - 6032. [Abstract] [Full Text] [PDF]
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U. Syrbe, S. Jennrich, A. Schottelius, A. Richter, A. Radbruch, and A. Hamann Differential regulation of P-selectin ligand expression in naive versus memory CD4+ T cells: evidence for epigenetic regulation of involved glycosyltransferase genes Blood, November 15, 2004; 104(10): 3243 - 3248. [Abstract] [Full Text] [PDF]
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R. R. Saff, E. S. Spanjaard, A. M. Hohlbaum, and A. Marshak-Rothstein Activation-Induced Cell Death Limits Effector Function of CD4 Tumor-Specific T Cells J. Immunol., June 1, 2004; 172(11): 6598 - 6606. [Abstract] [Full Text] [PDF]
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D. Masopust, V. Vezys, E. J. Usherwood, L. S. Cauley, S. Olson, A. L. Marzo, R. L. Ward, D. L. Woodland, and L. Lefrancois Activated Primary and Memory CD8 T Cells Migrate to Nonlymphoid Tissues Regardless of Site of Activation or Tissue of Origin J. Immunol., April 15, 2004; 172(8): 4875 - 4882. [Abstract] [Full Text] [PDF]
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E. I. Gergel and M. B. Furie Populations of Human T Lymphocytes That Traverse the Vascular Endothelium Stimulated by Borrelia burgdorferi Are Enriched with Cells That Secrete Gamma Interferon Infect. Immun., March 1, 2004; 72(3): 1530 - 1536. [Abstract] [Full Text] [PDF]
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H. Xu, A. Manivannan, H.-R. Jiang, J. Liversidge, P. F. Sharp, J. V. Forrester, and I. J. Crane Recruitment of IFN-{gamma}-Producing (Th1-Like) Cells into the Inflamed Retina In Vivo Is Preferentially Regulated by P-Selectin Glycoprotein Ligand 1:P/E-Selectin Interactions J. Immunol., March 1, 2004; 172(5): 3215 - 3224. [Abstract] [Full Text] [PDF]
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J. Huehn, K. Siegmund, J. C.U. Lehmann, C. Siewert, U. Haubold, M. Feuerer, G. F. Debes, J. Lauber, O. Frey, G. K. Przybylski, et al. Developmental Stage, Phenotype, and Migration Distinguish Naive- and Effector/Memory-like CD4+ Regulatory T Cells J. Exp. Med., February 2, 2004; 199(3): 303 - 313. [Abstract] [Full Text] [PDF]
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A. Schwarz, A. Maeda, M. K. Wild, K. Kernebeck, N. Gross, Y. Aragane, S. Beissert, D. Vestweber, and T. Schwarz Ultraviolet Radiation-Induced Regulatory T Cells Not Only Inhibit the Induction but Can Suppress the Effector Phase of Contact Hypersensitivity J. Immunol., January 15, 2004; 172(2): 1036 - 1043. [Abstract] [Full Text] [PDF]
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M. Bajenoff and S. Guerder Homing to Nonlymphoid Tissues Is Not Necessary for Effector Th1 Cell Differentiation J. Immunol., December 15, 2003; 171(12): 6355 - 6362. [Abstract] [Full Text] [PDF]
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C. Zaph and P. Scott Th1 Cell-Mediated Resistance to Cutaneous Infection with Leishmania major Is Independent of P- and E-Selectins J. Immunol., November 1, 2003; 171(9): 4726 - 4732. [Abstract] [Full Text] [PDF]
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W. Haddad, C. J. Cooper, Z. Zhang, J. B. Brown, Y. Zhu, A. Issekutz, I. Fuss, H.-o. Lee, G. S. Kansas, and T. A. Barrett P-Selectin and P-Selectin Glycoprotein Ligand 1 Are Major Determinants for Th1 Cell Recruitment to Nonlymphoid Effector Sites in the Intestinal Lamina Propria J. Exp. Med., August 4, 2003; 198(3): 369 - 377. [Abstract] [Full Text] [PDF]
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R. L. Reinhardt, D. C. Bullard, C. T. Weaver, and M. K. Jenkins Preferential Accumulation of Antigen-specific Effector CD4 T Cells at an Antigen Injection Site Involves CD62E-dependent Migration but Not Local Proliferation J. Exp. Med., March 17, 2003; 197(6): 751 - 762. [Abstract] [Full Text] [PDF]
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 A. E. Chang, Q. Li, G. Jiang, D. M. Sayre, T. M. Braun, and B. G. Redman Phase II Trial of Autologous Tumor Vaccination, Anti-CD3-Activated Vaccine-Primed Lymphocytes, and Interleukin-2 in Stage IV Renal Cell Cancer J. Clin. Oncol., March 1, 2003; 21(5): 884 - 890. [Abstract] [Full Text] [PDF]
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T. Hirata, B. C. Furie, and B. Furie P-, E-, and L-Selectin Mediate Migration of Activated CD8+ T Lymphocytes into Inflamed Skin J. Immunol., October 15, 2002; 169(8): 4307 - 4313. [Abstract] [Full Text] [PDF]
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R. A. Hawkins, R. G. Rank, and K. A. Kelly A Chlamydia trachomatis-Specific Th2 Clone Does Not Provide Protection against a Genital Infection and Displays Reduced Trafficking to the Infected Genital Mucosa Infect. Immun., September 1, 2002; 70(9): 5132 - 5139. [Abstract] [Full Text] [PDF]
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J. L. Curtis, J. Sonstein, R. A. Craig, J. C. Todt, R. N. Knibbs, T. Polak, D. C. Bullard, and L. M. Stoolman3 Subset-Specific Reductions in Lung Lymphocyte Accumulation Following Intratracheal Antigen Challenge in Endothelial Selectin-Deficient Mice J. Immunol., September 1, 2002; 169(5): 2570 - 2579. [Abstract] [Full Text] [PDF]
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I. Erdmann, E. P. Scheidegger, F. K. Koch, L. Heinzerling, B. Odermatt, G. Burg, J. B. Lowe, and T. M. Kundig Fucosyltransferase VII-Deficient Mice with Defective E-, P-, and L-Selectin Ligands Show Impaired CD4+ and CD8+ T Cell Migration into the Skin, but Normal Extravasation into Visceral Organs J. Immunol., March 1, 2002; 168(5): 2139 - 2146. [Abstract] [Full Text] [PDF]
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A. C. Issekutz and T. B. Issekutz The Role of E-Selectin, P-Selectin, and Very Late Activation Antigen-4 in T Lymphocyte Migration to Dermal Inflammation J. Immunol., February 15, 2002; 168(4): 1934 - 1939. [Abstract] [Full Text] [PDF]
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T. Katakai, K. J. Mori, T. Masuda, and A. Shimizu Selective accumulation of type 1 effector cells expressing P-selectin ligand and/or {alpha}4{beta}7-integrin at the lesions of autoimmune gastritis Int. Immunol., February 1, 2002; 14(2): 167 - 175. [Abstract] [Full Text] [PDF]
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D. J. Campbell and E. C. Butcher Rapid Acquisition of Tissue-specific Homing Phenotypes by CD4+ T Cells Activated in Cutaneous or Mucosal Lymphoid Tissues J. Exp. Med., January 7, 2002; 195(1): 135 - 141. [Abstract] [Full Text] [PDF]
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D. A. Carlow, S. Y. Corbel, M. J. Williams, and H. J. Ziltener IL-2, -4, and -15 Differentially Regulate O-Glycan Branching and P-Selectin Ligand Formation in Activated CD8 T Cells J. Immunol., December 15, 2001; 167(12): 6841 - 6848. [Abstract] [Full Text] [PDF]
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Y. Reiss, A. E. Proudfoot, C. A. Power, J. J. Campbell, and E. C. Butcher CC Chemokine Receptor (CCR)4 and the CCR10 Ligand Cutaneous T Cell-attracting Chemokine (CTACK) in Lymphocyte Trafficking to Inflamed Skin J. Exp. Med., November 19, 2001; 194(10): 1541 - 1547. [Abstract] [Full Text] [PDF]
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Y.-C. Lim, H. Xie, C. E. Come, S. I. Alexander, M. J. Grusby, A. H. Lichtman, and F. W. Luscinskas IL-12, STAT4-Dependent Up-Regulation of CD4+ T Cell Core 2 {beta}-1,6-n-Acetylglucosaminyltransferase, an Enzyme Essential for Biosynthesis of P-Selectin Ligands J. Immunol., October 15, 2001; 167(8): 4476 - 4484. [Abstract] [Full Text] [PDF]
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K. Tanigawa, N. Takeshita, R. A. Craig, K. Phillips, R. N. Knibbs, A. E. Chang, and L. M. Stoolman Tumor-Specific Responses in Lymph Nodes Draining Murine Sarcomas Are Concentrated in Cells Expressing P-Selectin Binding Sites J. Immunol., September 15, 2001; 167(6): 3089 - 3098. [Abstract] [Full Text] [PDF]
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G. Smithson, C. E. Rogers, P. L. Smith, E. P. Scheidegger, B. Petryniak, J. T. Myers, D. S. L. Kim, J. W. Homeister, and J. B. Lowe Fuc-TVII Is Required for T Helper 1 and T Cytotoxic 1 Lymphocyte Selectin Ligand Expression and Recruitment in Inflammation, and Together with Fuc-TIV Regulates Naive T Cell Trafficking to Lymph Nodes J. Exp. Med., August 27, 2001; 194(5): 601 - 614. [Abstract] [Full Text] [PDF]
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K. Singbartl, J. Thatte, M. L. Smith, K. Wethmar, K. Day, and K. Ley A CD2-Green Fluorescence Protein-Transgenic Mouse Reveals Very Late Antigen-4-Dependent CD8+ Lymphocyte Rolling in Inflamed Venules J. Immunol., June 15, 2001; 166(12): 7520 - 7526. [Abstract] [Full Text] [PDF]
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K. Hong, E. L. Berg, and R. O. Ehrhardt Persistence of Pathogenic CD4+ Th1-Like Cells In Vivo in the Absence of IL-12 but in the Presence of Autoantigen J. Immunol., April 1, 2001; 166(7): 4765 - 4772. [Abstract] [Full Text] [PDF]
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 A. Hamann and U. Syrbe T-cell trafficking into sites of inflammation Rheumatology, July 1, 2000; 39(7): 696 - 699. [Full Text] [PDF]
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T. M. Engeman, A. V. Gorbachev, R. P. Gladue, P. S. Heeger, and R. L. Fairchild Inhibition of Functional T Cell Priming and Contact Hypersensitivity Responses by Treatment with Anti-Secondary Lymphoid Chemokine Antibody During Hapten Sensitization J. Immunol., May 15, 2000; 164(10): 5207 - 5214. [Abstract] [Full Text] [PDF]
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C. Bartholdy, O. Marker, and A. R. Thomsen Migration of activated CD8+ T lymphocytes to sites of viral infection does not require endothelial selectins Blood, February 15, 2000; 95(4): 1362 - 1369. [Abstract] [Full Text] [PDF]
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B. A. Zabel, W. W. Agace, J. J. Campbell, H. M. Heath, D. Parent, A. I. Roberts, E. C. Ebert, N. Kassam, S. Qin, M. Zovko, et al. Human G Protein-coupled Receptor GPR-9-6/CC Chemokine Receptor 9 Is Selectively Expressed on Intestinal Homing T Lymphocytes, Mucosal Lymphocytes, and Thymocytes and Is Required for Thymus-expressed Chemokine-mediated Chemotaxis J. Exp. Med., November 1, 1999; 190(9): 1241 - 1256. [Abstract] [Full Text] [PDF]
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A. Chu, K. Hong, E. L. Berg, and R. O. Ehrhardt Tissue Specificity of E- and P-Selectin Ligands in Th1-Mediated Chronic Inflammation J. Immunol., November 1, 1999; 163(9): 5086 - 5093. [Abstract] [Full Text] [PDF]
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J. M. Blander, I. Visintin, C. A. Janeway Jr., and R. Medzhitov {alpha}(1,3)-Fucosyltransferase VII and {alpha}(2,3)-Sialyltransferase IV Are Up-Regulated in Activated CD4 T Cells and Maintained After Their Differentiation into Th1 and Migration into Inflammatory Sites J. Immunol., October 1, 1999; 163(7): 3746 - 3752. [Abstract] [Full Text] [PDF]
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S. Trembleau, G. Penna, S. Gregori, H. D. Chapman, D. V. Serreze, J. Magram, and L. Adorini Pancreas-Infiltrating Th1 Cells and Diabetes Develop in IL-12-Deficient Nonobese Diabetic Mice J. Immunol., September 1, 1999; 163(5): 2960 - 2968. [Abstract] [Full Text] [PDF]
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H. Xie, Y.-C. Lim, F. W. Luscinskas, and A. H. Lichtman Acquisition of Selectin Binding and Peripheral Homing Properties by CD4+ and CD8+ T Cells J. Exp. Med., June 7, 1999; 189(11): 1765 - 1776. [Abstract] [Full Text] [PDF]
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