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Center for Hemostasis and Thrombosis Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215
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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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4/
7 integrin is
expressed on gut-homing T cells (6), whereas cutaneous
lymphocyte Ag, which binds E-selectin, is preferentially expressed on T
cells migrating into skin (7).
Depending on the cytokines present during Ag priming,
CD4+ Th precursor cells differentiate toward Th1
or Th2 cells that produce distinct patterns of cytokines (8, 9). Recent studies have indicated that
CD8+ T cells can also be differentiated into
IFN-
-producing CD8+ type 1 cytotoxic T (Tc1)
cells or IL-4/IL-10-producing Tc2 cells (10, 11).
Differentiated Th1 and Th2 cells not only produce different sets of
cytokines, but also exhibit the preferential expression of adhesion
molecules and chemokine receptors, which may result in distinct
migration properties of these subsets (12, 13). Similarly,
Tc1 and Tc2 cells may differentially express adhesion molecules and
chemokine receptors (14). Differential selectin ligand
expression between type 1 and type 2 subsets was also reported for both
CD4+ and CD8+ T cells
(15, 16). It is speculated that these different migratory
properties of various T cell subsets are important for the efficient
regulation of the immune responses mediated by these effector
cells.
Contact hypersensitivity (CHS) is a T cell-mediated immune response induced by cutaneous application of a reactive hapten (17). During the sensitization phase, Langerhans cells migrate from epidermis to skin-draining lymph nodes, where they present hapten-MHC complexes to naive T cells. During the elicitation phase that develops after subsequent contact with the hapten, Ag-specific T cells migrate into the site of Ag challenge and release cytokines, thereby initiating the inflammatory response. CHS has long been considered a model of delayed-type hypersensitivity (DTH), which is mediated by CD4+ Th1 cells. Multiple studies suggest, however, that CHS responses are mediated by CD8+ Tc1 cells and down-regulated by CD4+ Th2 cells (18, 19, 20). The recent study using mice lacking either CD4+ or CD8+ T cells provided evidence that both CD4+ Th1 cells and CD8+ Tc1 cells function as effector cells in CHS responses (21). To exert effector functions, these cells need to migrate into the site of Ag challenge. The migration of in vitro-generated Th1 cells into the inflamed skin in a CHS model is mediated by P- and E-selectin (15). In addition, P-selectin glycoprotein ligand-1 (PSGL-1) on Th1 cells has been shown to function as a major P-selectin ligand and one of the E-selectin ligands (22, 23). However, the molecular mechanisms for CD8+ T cell trafficking into the inflamed skin have not been determined.
Here we investigated the migratory properties of CD8+ T cells into the inflamed skin in a CHS model using in vitro-generated Tc1 cells. Our results show that Tc1 cells are able to migrate into the inflamed skin and that the migration is partially mediated by P- and E-selectin. During P- and E-selectin-mediated migration, PSGL-1 on Tc1 cells functions as a predominant ligand for P-selectin and also plays a role as an E-selectin ligand. In addition, L-selectin mediates P- and E-selectin-independent migration of Tc1 cells. These results indicate roles for three selectins in CD8+ T cell migration into the inflamed skin.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice homozygous for the PSGL-1-targeted mutation (PSGL-1-/- mice) (24) were backcrossed five times with C57BL/6J (B6). B6 mice, P-selectin-deficient mice on a B6 background, B6 x 129S3/SvImJ (129S) F2 mice, and P- and E-selectin double-deficient mice on a B6/129S background were purchased from The Jackson Laboratory (Bar Harbor, ME). E-selectin-deficient mice on a B6 background were provided by Dr. A. Beaudet (Baylor College of Medicine, Houston, TX). All mice used were 8–12 wk old. The mice were housed in the animal facility of Beth Israel Deaconess Medical Center. All studies and procedures were approved by the Animal Care and Use Committee of Beth Israel Deaconess Medical Center.
Flow cytometry
All mAbs used in flow cytometric analyses were purchased from BD PharMingen (San Diego, CA). They include anti-CD4-PE (GK1.5), anti-CD8a-FITC (53-6.7), anti-CD8a-PE (53-6.7), anti-CD162-PE (2PH1), anti-CD62L-PE (MEL-14), anti-CD49d-PE (9C10), anti-CD18-PE (C71/16), anti-CD25-PE (PC61), anti-CD44-PE (IM7), and anti-CD45RB-PE (23G2). Cells were stained with mAbs for 30 min at 4°C, washed, and analyzed on a FACSCalibur (BD Biosciences, San Jose, CA) using CellQuest software (BD Biosciences). For assessment of selectin binding by flow cytometry, cells were incubated with selectin-IgM chimeras provided by Dr. J. Lowe (University of Michigan, Ann Arbor, MI) for 30 min at 4°C. Nonspecific binding was determined by the addition of 5 mM EDTA. Cells were then incubated with biotinylated goat anti-human IgM (American Qualex, San Clemente, CA) and stained with streptavidin-PE (BD Biosciences).
Cell culture
For generation of Tc1 and Tc2 cells, splenic
CD8+ T cells were isolated by negative selection
using the Mouse T Cell CD8 Subset Column Kit (R&D Systems, Minneapolis,
MN). Purified CD8+ T cells were cultured on
24-well tissue culture plates coated with 20 µg/ml anti-CD3
(145-2C11; R&D Systems) and 10 µg/ml anti-CD28 (37.51; BD
PharMingen) for 2 days in the presence of 4 ng/ml of IL-2 (R&D Systems)
and either 2 ng/ml IL-12 (R&D Systems) and 4 µg/ml anti-IL-4
(11B11; BD PharMingen) to promote Tc1 differentiation or 50 ng/ml IL-4
(Pierce Endogen, Rockford, IL) to promote Tc2 differentiation. After 2
days, the cells were transferred to uncoated plates and cultured for an
additional 4 days.
Analysis of cytokine production
After 5 days of culture, Tc1 or Tc2 cells were harvested,
washed, and restimulated with plate-coated anti-CD3 and
anti-CD28 for 24 h at 1 x 106
cells in 1 ml medium containing 4 ng/ml IL-2. Concentrations of IFN-
and IL-4 in the culture supernatants were determined by ELISA using
Quantikine M kits (R&D Systems).
Cell adhesion assays
Ninety-six-well plates (Flow Laboratories, McLean, VA) were coated with 10 µg/ml selectin-IgG chimeric proteins for 2 h at 37°C and blocked with 1% BSA overnight at 4°C as described previously (23). The cells were labeled with 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF; Molecular Probes, Eugene, OR) for 30 min at 37°C, washed, and resuspended in DMEM with 10% FCS. The labeled cells were added to each well (5 x 105/well) and incubated for 20 min at 4°C under rotation (60 rpm). The plates were washed three times with HBSS with CaCl2 and MgCl2, and bound cells were quantitated by measuring the fluorescence using a Cytofluor 2300 (Millipore, Bedford, MA). Each assay was conducted in triplicate and repeated three to six times.
Induction of CHS
Mice were sensitized by the application of 100 µl 2% (w/v) oxazolone (Sigma-Aldrich, St. Louis, MO) in acetone/olive oil (4/1; Sigma-Aldrich) solution on the shaved abdominal skin on day 0. Some mice were painted with acetone/olive oil alone. Mice were challenged on day 6 by applying 20 µl 0.5% (w/v) oxazolone in the same vehicle on the left ear (10 µl/side). The right ear was painted with the vehicle only. Ear swelling responses were confirmed by measuring ear thickness using a dial thickness gauge (Mitutoyo, Kanagawa, Japan).
Immunohistochemistry
Ear specimens were taken 24 h after challenge. Ears were severed from mice, embedded in OCT compound (Miles, Elkhart, IN), and frozen. Cryostat sections were fixed in acetone and stained for CD8 using rat anti-CD8 (Caltag Laboratories, Burlingame, CA), biotinylated rabbit anti-rat IgG (Vector Laboratories, Burlingame, CA), and ABC-alkaline phosphatasereagent (Vector Laboratories). Sections were also stained with MECA-79 (BD PharMingen), biotinylated anti-rat IgM, and avidin-biotin peroxidase complex-alkaline phosphatase reagent. Color was developed using Vector Red alkaline phosphatase substrate solution. Slides were counterstained with methylene green. The number of CD8+ T cell infiltrates was counted on 10 separate 0.1-mm2 regions/section. The sections were examined in a blinded fashion.
Isolation of skin-infiltrating cells
Skin-infiltrating cells were isolated via enzyme digestion as previously described (25). Briefly, ears taken 24 h after challenge were separated into ventral and dorsal sheets and incubated in HBSS containing 15% FCS and 1 mg/ml collagenase/dispase (Sigma) for 2 h at 37°C. The sheets were minced and disrupted on a 280-µm pore size stainless steel mesh (Bellco, Vineland, NJ) in cold HBSS. The resulting cell suspension was filtered sequentially through a 46-µm pore size stainless steel mesh (Bellco) and a 35-µm pore size nylon mesh filter (BD Falcon, Bedford, MA) and then washed twice in HBSS.
In vivo migration assays
Tc1 and Tc2 cells were harvested after 6 days of culture, and dead cells were removed by centrifugation on Histopaque 1083 (Sigma). The cells (1 x 107/ml) were radiolabeled with 100 µCi/ml sodium [51Cr]chromate (NEN Life Science Products, Boston, MA) for 1 h at 37°C in RPMI 1640 with 10% FCS. Cells were washed twice and resuspended in PBS. Cells (4 x 106) in 0.4 ml PBS were injected into the tail vein of a mouse that had been sensitized 7 days before and challenged on the left ear 24 h previously as described above. In some experiments anti-P-selectin (RB40.34; BD PharMingen), anti-E-selectin (9A9; provided by Dr. B. Wolitzky, Coelacanth, East Windsor, NJ), anti-L-selectin (MEL-14; BD PharMingen), anti-CD49d R1-2 (BD PharMingen) or PS/2 (Serotec, Oxford, U.K.), or isotype control (200 µg/mouse) was injected together with the cells. Mice were sacrificed 3 h after injection, the ears were removed, and the radioactivity in the skin was measured using a Packard gamma scintillation counter (Downers Grove, IL).
Statistical analysis
For statistical comparison of two samples, two-tailed Student’s t test was used.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD4+ T cell migration into the inflamed skin
is dependent on P- and E-selectin (15). To examine whether
P- and E-selectin mediate the migration of CD8+ T
cells into the inflamed skin, we examined cell infiltration into the
inflamed skin using an oxazolone-induced CHS model in mice lacking both
P- and E-selectin (P/E-/- mice). These mice are
reported to show impaired CHS response characterized by decreased ear
swelling and leukocyte accumulation (26).
P/E-/- mice and their control wild-type mice
were sensitized with 2 mg oxazolone on the shaved abdominal skin, and 6
days later they were challenged on the left ear with 100 µg
oxazolone. Some mice were painted with acetone-olive oil vehicle alone
at the time of sensitization to serve as unsensitized controls. Right
ears were painted with vehicle alone to serve as unchallenged control
ears. Similar to previous results (26), the ear swelling
response in P/E-/- mice measured 24 h
after challenge was decreased by 51% compared with that in wild-type
mice (P/E-/-, 12.3 ± 6.2 x
10-2 mm (n = 8); wild type,
25.0 ± 3.1 x 10-2 mm
(n = 8)). Immunohistochemical analyses of the skin
sections from the ears 24 h after challenge showed that
CD8+ T cell infiltrate in
P/E-/- mice was reduced by 79% compared with
that in wild-type mice (Fig. 1
). These
results suggest that P- and E-selectin play an important role in the
migration of CD8+ T cells into inflamed skin in a
CHS model.
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To directly determine whether CD8+ T cells
can migrate into the site of Ag challenge, the migratory behavior of in
vitro-stimulated CD8+ T cells was studied.
Enriched splenic CD8+ T cells were stimulated
with anti-CD3 and anti-CD28 either in the presence of IL-12,
anti-IL-4, and IL-2 to promote Tc1 differentiation or in the
presence of IL-4 and IL-2 for Tc2 differentiation. The cytokine
profiles of differentiated Tc1 and Tc2 cells were confirmed (data not
shown). Tc1 and Tc2 cells were labeled with 51Cr
and injected into the mice previously sensitized with oxazolone and
challenged on the left ear. The right ear was painted with the vehicle
and served as noninflamed control skin. Three hours after injection,
the radioactive cells that accumulated in the ear were measured. As
shown in Fig. 2A, Tc1 cells
migrated into the inflamed ear at a concentration 3 times higher than
Tc2 cells. No differences were observed between Tc1 and Tc2 cells in
the migration into the control ear. These results are similar to those
of CD4+ T cells that showed that Th1 cells
entered the inflamed skin in greater numbers than Th2 cells
(15). The migration of Tc1 cells into the inflamed skin,
however, was 39% lower than that of Th1 cells (Fig. 2B).
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To study which molecules are responsible for the differential
migration of Tc1 and Tc2 cells, we first examined adhesion molecule
expression on Tc1 and Tc2 cells. The expression of L-selectin (CD62L)
and 4 integrin (CD49d) is higher on Tc1 cells
than Tc2 cells, while PSGL-1 (CD162), 2
integrin (CD18), and CD44 are expressed at similar levels on both
subsets (Fig. 3A). Most
skin-infiltrating CD8+ T cells also appeared to
express PSGL-1, L-selectin, 4 integrin,
2 integrin, and CD44 (Fig. 3B).
This adhesion molecule expression profile is similar to that observed
with in vitro-differentiated Tc1 cells. Therefore, at least several
adhesion molecules are similarly expressed on
CD8+ T cells infiltrating the skin in vivo and in
vitro-differentiated CD8+ T cells.
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C). The adhesion profiles of Tc1 and Tc2 cells are
similar to those of Th1 and Th2 cells, respectively (Fig. 3C). No binding to L-selectin-IgG by Tc1 cells was
detectable (data not shown). Selectin binding of Tc1 and Tc2 cells was
also tested by flow cytometry. Fifty-eight percent of Tc1 cells bound
to P-selectin-IgM, and 81% bound to E-selectin-IgM, while 10 and 12%
of Tc2 cells bound to P-selectin-IgM and E-selectin-IgM, respectively
(Fig. 3D).
PSGL-1 on Th1 cells has been shown to be a ligand for P-selectin and in
part for E-selectin (23). We therefore tested whether
PSGL-1 on Tc1 cells functions as a ligand for P- and E-selectin. In
contrast to the binding of wild-type Tc1 cells to P-selectin-IgG, the
binding of PSGL-1-/- Tc1 cells to P-selectin
was almost completely absent (Fig. 3E). The binding of
PSGL-1-/- Tc1 cells to E-selectin was reduced
by 70% compared with that of wild-type Tc1 cells (Fig. 3E).
Therefore, PSGL-1 on Tc1 cells functions as a major ligand for
P-selectin and also plays a role in Tc1 cell binding to E-selectin in
vitro. The results are similar to those with Th1 cells
(23), suggesting that PSGL-1 on Th1 and Tc1 cells has
similar selectin-binding characteristics.
P- and E-selectin partially mediate Tc1 cell migration into the inflamed skin
To examine whether P- and E-selectin ligand expression observed in
vitro is relevant during the migration of Tc1 cells into the inflamed
skin, the cells were injected into P/E-/- mice
previouslysensitized and challenged with oxazolone. The
migration of Tc1 cells into inflamed skin of
P/E-/- mice was reduced by 59% compared with
the migration into inflamed skin of wild-type mice (Fig. 4A). The migration of Tc1
cells was also reduced when the cells were injected into
wild-type mice with the combination of anti-P- and
anti-E-selectin Abs (Fig. 4B). These results indicate
that P- and E-selectins are involved in the migration of Tc1 cells into
inflamed skin. However, we observed a considerably greater accumulation
of Tc1 cells in the inflamed skin of P/E-/-
mice or wild-type mice treated with anti-P- and anti-E-selectin
Abs compared with Th1 cells (Fig. 4), suggesting the existence of a P-
and E-selectin-independent mechanism of Tc1 cell migration.
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The in vitro adhesion assays showed that PSGL-1 on Tc1 cells is a
ligand for P-selectin and also functions as a ligand for E-selectin. To
study the role of PSGL-1 in Tc1 cell migration in vivo, the migrations
of wild-type and PSGL-1-/- Tc1 cells to the
inflamed skin of wild-type mice were compared. A slightly reduced
migration of PSGL-1-/- Tc1 cells to the
inflamed skin of wild-type mice on both B6 and B6/129S backgrounds was
observed, although the reduction was not statistically significant
(Fig. 5).
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A). This indicates that PSGL-1 does not play a role during
P- and E-selectin-independent migration and thus implies a role for
PSGL-1 during P- and E-selectin-dependent migration. Indeed, when the
cells were injected into sensitized and challenged E-selectin-deficient
(E-/-) mice, the migration of
PSGL-1-/- Tc1 cells was reduced to the level of
P- and E-selectin-independent migration (Fig. 5B). Thus, it
appears that PSGL-1 on Tc1 cells is the major ligand for P-selectin
in vivo.
In contrast, when PSGL-1-/-
Tc1 cells were injected into P-selectin-deficient
(P-/-) mice, the migration was not reduced to
the level of P- and E-selectin-independent migration (Fig. 5B). Therefore, it is likely that there are E-selectin
ligands other than PSGL-1, although PSGL-1 functions as one of the
E-selectin ligands.
P- and E-selectin-independent migration of Tc1 cells into inflamed skin is mediated predominantly by L-selectin
We sought to identify the molecules mediating P- and
E-selectin-independent migration of Tc1 cells into inflamed skin. Based
on the observation that 4 integrin and
L-selectin are expressed at high levels on Tc1 cells (Fig. 3A), we examined P- and E-selectin-independent Tc1 cell
migration in the presence of function-blocking Abs against
4 integrin or L-selectin.
4 integrin has been suggested to mediate
lymphocyte rolling (27). However, neither mAb PS/2 nor
R1-2 against 4 integrin had any effect on Tc1
cell migration into the inflamed skin of P/E-/-
mice (Fig. 6A), indicating
that 4 integrin is not involved in the P- and
E-selectin-independent process of Tc1 cell migration into inflamed
skin. In contrast, the anti-L-selectin mAb MEL-14 inhibited the
migration by 44% compared with its isotype control (Fig. 6B). The inhibitory effect of MEL-14 was not observed when
the migration was examined in wild-type mice, most likely due to the
compensation by P- and E-selectin (data not shown). These data suggest
that L-selectin is involved in the migration of Tc1 cells into inflamed
skin. Taken together, all three selectins can mediate the migration of
Tc1 cells into the inflamed skin in this model.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As an experimental model we used an oxazolone-induced CHS response,
which is a widely used model of a T cell-mediated response. Although a
large number of studies have focused on the respective roles of
CD4+ and CD8+ T cells in
CHS, conflicting results have been reported. CHS is thought to
represent a model of DTH, which is mediated by
CD4+ Th1 cells. However, recent studies
demonstrated that IFN--producing CD8+ Tc1
cells play an effector role in this model. Although the exact
mechanisms of whether CD4+ Th1 or
CD8+ Tc1 cells predominate as effector cells and
their differential roles have not been well clarified, in a study of
human nickel allergy, CD8+ Tc1 cells have been
implicated in the initiation of tissue damage, while
CD4+ Th1 cells are implicated in a later phase,
based on results showing disparate cytotoxic activity of
CD4+ and CD8+ T cell
subsets against keratinocytes (28). As both
CD4+ Th1 and CD8+ Tc1 cells
have been shown to function as effector cells in CHS responses to
dinitrofluorobenzene and oxazolone, these cells may have similar
differential roles. In an oxazolone-induced CHS model, we showed that
in vitro-generated Tc1 cells were able to migrate into the inflamed
skin, but not into the control skin. Our data also showed that Tc1
cells migrated more efficiently into the inflamed skin than Tc2 cells,
just as Th1 cells migrated more efficiently than Th2 cells
(15). The differential migration between type 1 and type 2
cells into inflamed skin may be explained by their differential
expression of ligands for P- and E-selectin: type 1 cells express more
functional ligands for P- and E-selectin than type 2 cells. It is still
possible that the expression of other adhesion molecules and chemokine
receptors affects the differential migration between Tc1 and Tc2 cells.
Indeed, different chemokine receptor expression patterns are observed
between Tc1 and Tc2 cells (14).
The expression of functional selectin ligands during Th cell
differentiation in vitro appears to be regulated by the cytokine
milieu; the Th1 cytokine IL-12 up-regulates functional selectin ligands
through (1, 3)-fucosyltransferase VII (Fuc-T VII), while the Th2
cytokine IL-4 down-regulates Fuc-T VII (29, 30). As IL-12
directs the differentiation of either CD4+ or
CD8+ T cells into effector populations that
express functional selectin ligands, it is likely that the same
mechanism through Fuc-T VII regulates selectin ligand expression on
CD8+ T cells. Indeed, Fuc-T VII is required for
selectin ligand expression on Tc1 cells (31). PSGL-1 on
Th1 cells is the glycoprotein core that is post-translationally
modified by Fuc-T VII and other enzymes to function as a major
P-selectin ligand and one of the E-selectin ligands. Our in vitro
adhesion assays show that PSGL-1 on Tc1 cells is the predominant ligand
for P-selectin and also plays a role as one of the ligands for
E-selectin. The in vivo migration assays support this observation.
Thus, the role of PSGL-1 on Tc1 cells is very similar to that on Th1
cells. In vivo, the expression of functional selectin ligands is also
dependent on the local environment, and selectin ligand-expressing
lymphocytes are found particularly in cutaneous inflammatory sites
(32, 33).
In contrast to Th1 cells that depend almost completely on P- and E-selectin to migrate into the inflamed skin, absence of P- and E-selectin caused only partial inhibition of Tc1 cell migration. We show that the P- and E-selectin-independent migration of Tc1 cells was predominantly mediated by L-selectin. This may be explained by the presence of a cell population within Tc1 cells that does not have selectin-binding activities and yet has the capacity to migrate into inflamed skin. Alternatively, the cooperative function of P- and E-selectin ligands with L-selectin on Tc1 cells is required for efficient migration. Such cooperative functioning of all three selectins has been demonstrated for neutrophil rolling on cytokine-activated endothelium (34).
Although L-selectin is primarily a lymphocyte homing receptor that mediates the tethering and rolling of lymphocytes on HEVs within lymph nodes, its role in lymphocyte recruitment into inflamed tissues has also been suggested. MEL-14 can block lymphocyte migration into a DTH-like site produced by sensitization and challenge to Bordetella pertussis vaccine (35). L-selectin has also been shown to be involved in lymphocyte migration to cutaneous site of inflammation in an allogenic skin graft model (36) and to inflamed lacrimal glands (37). The Tc1 cells used in our studies express L-selectin at high levels. Although naive T cells down-regulate L-selectin following activation, there is heterogeneity of effector and memory cells, and both L-selectin high and low populations have been reported.
The involvement of L-selectin in Tc1 cell migration further suggests that L-selectin ligands may be expressed on skin vessels at sites of inflammation. HEV ligands for L-selectin, collectively called PNAd, are stained with mAb MECA-79. In certain chronic skin diseases, postcapillary venules of the skin are reactive with MECA-79, suggesting that L-selectin ligands can be expressed not only on peripheral node HEVs, but also on skin endothelial cells (38, 39). Although the skin vessels in this oxazolone-induced CHS model were negative for MECA-79 (data not shown), the existence of MECA-79-unreactive L-selectin ligands has also been suggested (40).
4 integrin has been shown to play a role in
lymphocyte rolling and migration. Both selectin ligands and
4 integrin participate in T lymphoblast
recruitment during the pulmonary immune response (41).
Although in vitro-generated Tc1 cells express
4 integrin at high levels,
anti-4 integrin mAb administration had no
effect during P- and E-selectin-independent migration, suggesting that
4 integrin is not involved in Tc1 cell
migration in this model. In this regard, it is of note that in
vitro-differentiated human Th2 cells, but not Th1 cells, are capable of
interacting with VCAM-1, although both subsets express
4 integrin (42).
CD8+ cytotoxic cells are major effector cells of the immune defense system against viruses and tumors. The migration of Tc1 effector cells to infected sites during viral infection does not require P- and E-selectin (43). Tissue specificity of selectin ligands has been shown for Th1 cells (33). Thus, it is likely that selectins may be important for Tc1 cell migration into the inflamed skin, but may not be required for migration to other tissues. It is speculated that different sets of molecules mediate Tc1 cell migration to different sites of inflammation.
In conclusion, our data show that all three selectins can mediate the migration of Tc1 cells into the inflamed skin, with P- and E-selectin playing the dominant roles, and L-selectin playing a role in the absence of P- and E-selectin. As CD8+ T cells are found in lesions of a variety of human skin diseases, such as psoriasis, allergic contact dermatitis, atopic dermatitis, and cutaneous graft-vs-host disease, and play a critical role in the development and course of these diseases (44), selectins are possible targets for therapeutic modulation of these conditions.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Bruce Furie, Research East #319, Beth Israel Deaconess Medical Center, P.O. Box 15732, Boston, MA 02215. E-mail address: bfurie{at}caregroup.harvard.edu
3 Abbreviations used in this paper: PNAd, peripheral node addressin; BCECF, 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein; CHS, contact hypersensitivity; DTH, delayed-type hypersensitivity; Fuc-T VII, (1,3)-fucosyltransferase VII; HEVs, high endothelial venules; PSGL-1, P-selectin glycoprotein ligand-1; Tc1 cells, CD8+ type 1 cytotoxic T cells.
Received for publication January 30, 2002. Accepted for publication August 2, 2002.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-producing (Tc1) effector CD8+ T cells and interleukin (Il) 4/Il-10-producing (Th2) negative regulatory CD4+ T cells. J. Exp. Med. 183:1001.41 integrin, peripheral node addressin/l-selectin, and lymphocyte function-associated antigen-1 adhesion pathways. Am. J. Pathol. 159:671.41-integrin activation is necessary for high-efficiency T-cell subset interactions with VCAM-1 under flow. Microcirculation 7:201.[Medline]
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 V. Carriere, R. Colisson, C. Jiguet-Jiglaire, E. Bellard, G. Bouche, T. Al Saati, F. Amalric, J.-P. Girard, and C. M'Rini Cancer Cells Regulate Lymphocyte Recruitment and Leukocyte-Endothelium Interactions in the Tumor-Draining Lymph Node Cancer Res., December 15, 2005; 65(24): 11639 - 11648. [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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J. J. Garcia-Vallejo, W. van Dijk, I. van Die, and S. I. Gringhuis Tumor Necrosis Factor-{alpha} Up-regulates the Expression of {beta}1,4-Galactosyltransferase I in Primary Human Endothelial Cells by mRNA Stabilization J. Biol. Chem., April 1, 2005; 280(13): 12676 - 12682. [Abstract] [Full Text] [PDF]
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M. Martinez, M. Joffraud, S. Giraud, B. Baisse, M. P. Bernimoulin, M. Schapira, and O. Spertini Regulation of PSGL-1 Interactions with L-selectin, P-selectin, and E-selectin: ROLE OF HUMAN FUCOSYLTRANSFERASE-IV AND -VII J. Biol. Chem., February 18, 2005; 280(7): 5378 - 5390. [Abstract] [Full Text] [PDF]
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 A. van Zante, J.-M. Gauguet, A. Bistrup, D. Tsay, U. H. von Andrian, and S. D. Rosen Lymphocyte-HEV Interactions in Lymph Nodes of a Sulfotransferase-deficient Mouse J. Exp. Med., November 3, 2003; 198(9): 1289 - 1300. [Abstract] [Full Text] [PDF]
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C. B. Fieger, C. M. Sassetti, and S. D. Rosen Endoglycan, a Member of the CD34 Family, Functions as an L-selectin Ligand through Modification with Tyrosine Sulfation and Sialyl Lewis x J. Biol. Chem., July 25, 2003; 278(30): 27390 - 27398. [Abstract] [Full Text] [PDF]
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M. Sperandio, M. L. Smith, S. B. Forlow, T. S. Olson, L. Xia, R. P. McEver, and K. Ley P-selectin Glycoprotein Ligand-1 Mediates L-Selectin-dependent Leukocyte Rolling in Venules J. Exp. Med., May 19, 2003; 197(10): 1355 - 1363. [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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