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(1,3)-Fucosyltransferase VII in Activated CD4+ T Cells by TGF-ß1 Through a p38 Mitogen-Activated Protein Kinase-Dependent Pathway1
Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(1,3)-fucosyltransferase VII (FucT-VII), a FucT
essential for biosynthesis of selectin ligands. FucT-VII is sharply
induced in activated T cells by IL-12, but cytokines other than IL-12
that induce FucT-VII and functional selectin ligands have not been
identified, and are likely to be important in homing of T cells to
other selectin-dependent sites. Screening of a number of cytokines
known to be active on T cells identified only TGF-ß1 as able to
up-regulate FucT-VII mRNA levels and selectin ligands on activated CD4
T cells. The sharp increase in FucT-VII induced by TGF-ß1 in
activated T cells was completely blocked by pharmacologic inhibition of
p38 mitogen-activated protein kinase, but was unaffected by
mitogen-activated protein/extracellular signal-related kinase kinase
inhibitors. The selective ability of TGF-ß1 to induce selectin
ligands on activated T cells is likely important for T cell homing to
the gut, which is a strongly selectin-dependent site, and correlates
with the ability of TGF-ß1 to coordinately induce other
gut-associated homing pathways. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Blood neutrophils and other myeloid cells constitutively express both
L-selectin and high levels of functional ligands for both E- and
P-selectin. In contrast, naive T cells express L-selectin, but no
detectable functional ligands for the endothelial selectins. However,
Th1 cells express high levels of ligands for the endothelial selectins
(3, 7, 8), a phenotype attributable in part to the
expression of (1, 3)-fucosyltransferase VII
(FucT-VII),5 a FucT
well documented to be essential for biosynthesis of selectin ligands
(9, 10). Recent work in this laboratory and others has
shown that levels of FucT-VII mRNA and activity are strongly
up-regulated in activated T cells by IL-12 (7, 8).
Maintenance of L-selectin expression, which is essential for homing of
lymphocytes from the blood across high endothelial venule into
peripheral lymph nodes, may also be controlled by IL-12
(11). Because secretion of IL-12 by dendritic cells is
generally induced by cutaneous infection, the homing ability of T cells
responding to pathogens encountered in the skin is likely to be
controlled to a significant extent by IL-12 through effects on FucT-VII
expression.
Cytokines which control selectin ligand expression in the context of
homing to the gut and gut-associated lymphoid tissue have not been
identified, although TGF-ß1 is a candidate for this function.
TGF-ß1 is well established as an important factor for isotype
switching of B cells to IgA, a key component in mucosal immunity.
TGF-ß1 is also well known to alter the profile of integrins on
activated T cells from a LFA-1high/VLA-4high
"peripheral blood" phenotype to a
LFA-1low/VLA-4low/human mucosal lymphocyte-1
(Eß7)high
"mucosal" phenotype (12, 13). In this report, we
tested whether TGF-ß1 or other cytokines that affect the phenotype
and function of activated T cells could induce FucT-VII and functional
ligands for the endothelial selectins.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mAb used in these studies were as follows: S3.1 (anti-CD4), 7D6 (anti-CD3), and UCHL-1 (anti-CD45RO; all kindly supplied by Dr. Edgar G. Engleman (Stanford University, Stanford, CA)), 2H4 (anti-CD45RA; Coulter Immunology, Hialeah, FL), OKT3 (anti-CD3; American Type Culture Collection, Manassas, VA), anti-CD28 (R&D Systems, Minneapolis, MN), MECA-79 (American Type Culture Collection), HECA-452 (anti-CLA; American Type Culture Collection), goat anti-mouse IgM or IgG (Biosource, Camarillo, CA), and goat anti-human IgM (Sigma, St. Louis, MO). Chinese hamster ovary (CHO)/E-selectin and CHO/P-selectin transfectants were as described (7).
Isolation of naive CD4+ T cells
PBMC were isolated from human buffy coat leukocytes of anonymous donors by Ficoll-Hypaque (Histopaque, Sigma) centrifugation and recovery of cells at the interface. T cells were isolated from PBMC by rosetting with neuraminidase-treated sheep RBC. CD4+ T lymphocytes were isolated from this T cell-enriched population by panning with anti-CD4, and were >98% CD4+. Naive CD4+ T cells were isolated by magnetic activated cell sorting of the purified CD4+ T cells after labeling with anti-CD45RA magnetic beads (Miltenyi Biotech, Auburn, CA). Naive CD4+ T cells were >98% CD45RA+ and <5% CD45R0+.
T cell activation cultures
CD4+ T cells (4 x
106) in 2 ml of RPMI 1640 (Life Technologies,
Rockville, MD) containing 5% FCS, 1% penicillin/streptomycin, and 2
mM L-glutamine (complete media (CM)) were activated on
24-well plates precoated with 1 µg/ml anti-CD3 plus anti-CD28
mAb (anti-CD3/CD28) for 48 h, exactly as described
(7). Where indicated, cultures contained 2 ng/ml TGF-ß1
(Biosource) throughout the activation protocol. After 48 h, cells
were removed from mAb-coated wells, washed, and diluted to 5 x
105 cells/ml in CM containing 10 U/ml recombinant
human (rh)IL-2 (Biosource) ± 2 ng/ml TGF-ß1. Cell concentration
was maintained at 5 x 105 cells/ml by
diluting the cultures daily with fresh cytokine-containing media. Cells
were removed from cultures at various timepoints for analysis. Where
indicated, otherwise identical cultures contained one of the following
cytokines instead of TGF-ß1: 0.2 ng/ml rhIL-12, 1000 U/ml rhTNF-
(both from R&D Systems), 1500 U/ml rhIFN-, 100 ng/ml rhIL-10, 25
ng/ml IL-11, 1000 U/ml rhIFN-
, 100 ng/ml rhIL-6 (all from
Biosource), 10 ng/ml rhIL-13, or 30 ng/ml rhIL-18 (both from PeproTech,
Rocky Hill, NJ). Preliminary experiments (not shown) established that
the effects of TGF-ß1 on T cell FucT-VII expression were independent
of the presence or absence of IL-2. Therefore, we included IL-2 in all
cultures starting at day 2 to enhance T cell viability and
recovery.
For assays involving mitogen-activated protein kinase (MAPK) inhibitors, cells were activated on mAb-coated plates as above without cytokines or inhibitors. After 48 h, cells were removed from the plates and diluted to 5 x 105 cells/ml in CM containing 10 U/ml rhIL-2 ± TGF-ß1 ± MAPK inhibitors, as indicated. Delayed addition of MAPK inhibitors was required to avoid blocking T cell activation by anti-CD3/CD28 (data not shown). The MAP/extracellular signal-related kinase (ERK) kinase inhibitor PD98059 (New England Biolabs, Beverly, MA) or the p38 MAPK inhibitor SB203580 (Calbiochem, La Jolla, CA) were used at 20 µM. Under these conditions, MAPK inhibitors did not decrease T cell viability, as compared with control cells treated with an equal volume of vehicle.
Semiquantitative RT-PCR
Detection of FucT-VII, C2GnT, and PGK1 mRNA by RT-PCR was as described (7). Briefly, total cellular RNA was isolated from 107 cells, and 1 µg total RNA was used as template in a 20-µl RT reaction. PCR amplification of cDNA was conducted with cycle numbers previously titered to be well below the plateau phase of amplification, to give an accurate reflection of the relative starting concentration of mRNA. For C2GnT and PGK1 detection, 25 cycles were used, and for FucT-VII detection, 30 cycles were used. Cycle parameters and primer sequences were as described (7). To enhance comparisons between different groups of activated CD4+ T cells, PCR were conducted as above using 2-fold serial dilutions of the input cDNA. PCR products were detected by agarose gel electrophoresis and Southern blotting, as described (7).
Flow cytometry
FACS analysis to analyze expression of CLA (HECA-452 mAb) or ligands for E- or P-selectin, using selectin/IgM chimeras (9), or purity of isolated subpopulations of T cells, was as described (7). Data were collected on a FACScalibur flow cytometer (Becton Dickinson, Mountain View, CA) and analyzed with CellQuest software (Becton Dickinson). Data are presented as the percent of cells staining for the indicated epitope based on the position of the negative control histogram.
In vitro rolling assays
Adhesion of cells to E- or P-selectin was determined in a parallel plate flow chamber (CytoDyne, San Diego, CA) at a shear stress of 1.9 dyne/cm2, exactly as described (7). T cells rolling on monolayers of CHO cell transfectants expressing either E-selectin or P-selectin were recorded on videotape for offline analysis. Data are expressed as numbers of interacting cells/field/min, and are averaged for at least 10 different fields of view.
Statistical analysis
Adhesion data were analyzed by Student’s t test. Differences were considered statistically significant with p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We and others have previously shown that FucT-VII and ligands for
endothelial selectins are coordinately up-regulated in activated T
cells by IL-12, and down-regulated by IL-4 (7, 8).
Therefore, we screened a number of other cytokines known to be active
on T cells for their effect on expression of FucT-VII, as determined by
staining with the HECA-452 mAb, which on human T cells serves as a
FucT-VII reporter epitope (10, 14). As we showed
previously, IL-12 strongly up-regulated the level of HECA-452 staining
(Fig. 1
). In addition, as low as 2 ng/ml
TGF-ß1 potently up-regulated HECA-452 staining (Fig. 1). In sharp
contrast, none of the other cytokines tested up-regulated HECA-452
staining above that associated with TCR engagement alone. Importantly,
IL-2 had no effect, either alone or in combination with other cytokines
(Fig. 1 and data not shown), although addition of IL-2 to cultures
improved cell yield and viability. Similarly, a number of other
cytokines, including IL-6, IL-11, IL-10, IL-13, IFN-, IL-18,
TNF-, and IFN-, were without effect (Fig. 1). Maximal induction
of HECA-452 staining in response to TGF-ß1 exceeded the levels
reached with IL-12, and up-regulation of HECA-452 staining on
TGF-ß1-treated naive CD4+ T cells was also more
rapid than that seen with IL-12 (Fig. 2),
suggesting that TGF-ß1 is more potent than IL-12. These data
demonstrate that IL-12 and TGF-ß1 selectively and directly induce or
augment FucT-VII expression in CD4+ T cells.
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We compared the effects of TGF-ß1 on naive and memory CD4 cells.
Activation of naive CD4+ T cells by plate-bound
anti-CD3/CD28 alone in the absence of any exogenous cytokines led
to a small but reproducible increase in HECA-452 staining (from 
4%+
to 8–10%+; Fig. 3). On memory
CD4+ cells, where activation through the TCR
alone produced a significant increase in HECA-452 staining, this level
was nonetheless significantly augmented by TGF-ß1 (Fig. 3; note scale
difference). These data indicate that TGF-ß1 is a potent inducer of
FucT-VII in activated CD4+ T cells.
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We next examined by semiquantitative RT-PCR the levels of mRNA for
FucT-VII and for C2GnT, an O-linked branching enzyme also
required for selectin ligand biosynthesis (15) in naive
CD4+ T cells activated in the presence or absence
of TGF-ß1 (Fig. 4). Naive resting
CD4+ T cells do not express FucT-VII and have low
levels of C2GnT (Ref. 7 ; Fig. 4). Compared with cells
activated without TGF-ß1, cells activated in the presence of TGF-ß1
expressed significantly higher levels of both FucT-VII and C2GnT mRNA
(Fig. 4). These results indicate that TGF-ß1 exerts its effects on
steady-state mRNA levels. At least for FucT-VII, mRNA for which is not
detectable in naive CD4 cells, this implies that this inductive effect
of mRNA levels is at least partly transcriptional, but does not rule
out post transcriptional mechanisms such as enhancement of mRNA
stability.
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We analyzed the ability of TGF-ß1 to induce functional selectin
ligands, concomitant with its ability to up-regulate expression of
FucT-VII and C2GnT mRNA. Naive CD4+ T cells
activated in the presence of TGF-ß1 exhibited a significant increase
in the number of cells which express functional ligands for both E- and
P-selectin (Figs. 5 and 6). Kinetic analysis of selectin ligand
expression using binding of E-RIgM or P-RIgM showed that the response
to TGF-ß1 peaks at approximately day 5, whereas the much lower
response to TCR engagement alone peaks earlier (Fig. 5). Analysis of
the ability of these cells to attach and roll on E- and P-selectin
showed a significant increase in the ability of TGF-ß1-treated cells
to roll on both selectins, compared with naive CD4 cells activated
without TGF-ß1 (Fig. 6), corresponding to the selectin chimera
binding data. Therefore, the selective up-regulation of both FucT-VII
and C2GnT by TGF-ß1 is associated with a corresponding increase in
the ability of activated CD4+ T cells to interact
with endothelial selectins.
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To begin to explore signal transduction pathways which control the expression of FucT-VII in activated T cells, we examined the effects of MAPK inhibitors on the up-regulation of FucT-VII activity by TGF-ß1. Preliminary experiments revealed that inclusion of MAPK inhibitors at the initiation of culture prevented T cell activation and drastically reduced T cell viability (data not shown). Therefore, naive CD4+ T cells were activated by anti-CD3/CD28 for 2 days in the absence of TGF-ß1 or MAPK inhibitors, and were subsequently cultured with IL-2, with or without 2 ng/ml TGF-ß1, in the presence or absence of specific pharmacologic inhibitors of either p38 MAPK (SB203580) or MAP/ERK kinase 1/2 (PD98059). Under these conditions, no loss of viability due to the presence of the MAPK inhibitors was observed, and cell recovery from cultures with or without MAPK inhibitors was not significantly different, suggesting that T cell activation and proliferation was not generally inhibited by the addition of MAPK inhibitors. FucT-VII expression was analyzed over time by HECA-452 staining.
Strikingly, the TGF-ß1-induced increase in HECA-452 staining was
abrogated by SB203580 (Fig. 7A). HECA-452 staining of CD4
cells from cultures containing 20 µM SB203580 was indistinguishable
from cultures activated in the absence of TGF-ß1. In contrast, the
TGF-ß1-induced up-regulation of HECA-452 staining was unaffected by
PD98059 (Fig. 7B). These data implicate p38 MAPK pathways in
TGF-ß1-induced up-regulation of FucT-VII expression in activated
CD4+ T cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The absence of any effect of an array of cytokines tested here on
FucT-VII expression underscores the selectivity with which cytokines
control FucT-VII expression, and has important and specific
implications for molecular mechanisms controlling FucT-VII expression
in activated CD4+ T cells. First, the observation
that IFN-, which like IL-12 activates Stat4 in human T cells
(16), had no effect on FucT-VII expression (Fig. 1
),
suggests that activation of Stat4 is not sufficient for induction of
FucT-VII mRNA. Second, the finding that neither IL-18, which like IL-12
can induce IFN- expression (17), nor IFN- itself,
had any effect makes it unlikely that IL-12 induces FucT-VII expression
via an autocrine mechanism involving IFN-. Similarly, TNF-, which
is also produced by Th1 cells, had no effect on HECA-452 staining (Fig. 1A), making it similarly unlikely that IL-12 induces
FucT-VII expression through autocrine induction of TNF-. Perhaps
most interestingly, IL-13, which shares receptor chains with IL-4 and
which is also involved in Th2 development (18, 19),
nonetheless had no effect on FucT-VII expression despite the ability of
IL-4 to inhibit FucT-VII expression. Finally, IL-10, which like IL-4 is
secreted by Th2 cells and often exhibits an inhibitory effect on T cell
responses, particularly Th1 development (20), did not
affect FucT-VII expression (Fig. 1A). These data demonstrate
that IL-12 and TGF-ß1 selectively and directly augment FucT-VII
expression in activated CD4+ T cells.
A recent report suggests that TGF-ß1 antagonizes signaling intiated
by IL-12 in CD4 T cells, and that this antagonism is associated with
decreased tyrosine phosphorylation of both JAK and Stat4 proteins and
diminished IFN- production (21). However, TGF-ß1 and
IL-12 each strongly up-regulate FucT-VII expression in CD4 T cells
(this report and Ref. 7). Moreover, suboptimal doses of
TGF-ß1 synergize with low doses of IL-12 for induction of FucT-VII
during activation of naive CD4 cells (data not shown). Taken together
with the observation that activation of Stat4 by IFN- had no effect
on FucT-VII expression, these findings strengthen the hypothesis that
activation of Stat4 is not sufficient for, and may not even be involved
in, induction of FucT-VII in activated CD4 cells.
Although TGF-ß1 is well established to have several important
functions in mucosal immunity, including class switching to IgA by
activated B lymphocytes and induction of integrins associated with gut
homing and retention (12, 13), signal transduction
pathways associated with these events have not been defined.
Transcriptional induction of target genes by TGF superfamily ligands
generally involves activation of SMAD transcription factors
(22), but TGF-ß1 can also activate genes in a
MAPK-dependent fashion independent of participation by SMADs
(23). Therefore, we examined the effects of MAPK
inhibitors on the up-regulation of FucT-VII activity by TGF-ß1. The
data indicate that induction of FucT-VII in activated
CD4+ T cells by TGF-ß1 is selectively dependent
on p38 MAPK, but not on MAP/ERK kinase. Further, because SB203580
inhibits p38 and p38ß, but not p38 or p38
(24),
and because p38ß is expressed only at very low levels in CD4 cells
(25), these data directly implicate p38 as the
principal MAPK responsible for TGF-ß1-induced up-regulation of
FucT-VII mRNA in activated CD4 T cells. Activation of p38 MAPK by
TGF-ß1 through TAK1 and MKK6 has been demonstrated in
nonhematopoietic cells (26). Whether this pathway is
operative in activated T cells remains to be established. These
findings establish FucT-VII as the first gene, to our knowledge, that
is induced by TGF-ß1 via a MAPK-dependent mechanism in cells of the
immune system, and implicate a limited number of transcription factors
downstream of p38 MAPK in the regulation of FucT-VII expression in
activated CD4+ T cells.
Prior or concurrent TCR engagement was required for the up-regulation
of FucT-VII mRNA by both IL-12 and TGF-ß1, as no effects of these
cytokines were observed on resting cells (data not shown). Coupling
cytokine-driven acquisition of homing responses to T cell activation
ensures that principally Ag-specific cells will initially localize to a
peripheral site of inflammation. However, we should emphasize that
engagement of the TCR in the absence of exogenous cytokines induced a
low but detectable level of FucT-VII expression in naive CD4 cells.
This effect of TCR engagement was enhanced in memory CD4 cells,
consistent with the enhanced response of memory T cells to TCR
engagement. Therefore, signals emanating from the TCR are essential for
induction or up-regulation of FucT-VII expression by IL-12 or TGF-ß1.
For IL-12, this requirement is likely associated with (at least) de
novo induction of the IL12Rß2 chain and consequent responsiveness to
IL-12. For TGF-ß1, the pattern of expression of the receptor chains
TßRI and TßRII on T cells is unknown. It is possible that IL-12 and
TGF-ß1 act principally to amplify signal transduction pathways
initiated by TCR engagement, or that independent signals from both the
TCR and cytokine receptors are required for maximal induction of
FucT-VII mRNA levels. Whether these cytokines act at a
posttranscriptional level to maintain FucT-VII mRNA levels
(27) is also not yet clear. The present data does not
allow us to distinguish transcriptional from posttranscriptional
mechanisms. However, the ability to temporally segregate TCR engagement
from cytokine-mediated induction of FucT-VII (Fig. 4), and the absence
of detectable FucT-VII mRNA in naive CD4 cells (7)
suggests that both IL-12 and TGF-ß1 can directly induce or enhance
FucT-VII transcription in activated T cells.
Our results support a new model in which different cytokines control homing programs of effector T cell migration to distinct target tissues. Naive T cells responding to Ag-bearing dendritic cells, which have entered peripheral lymph nodes in response to Ag encountered in the skin, are likely to see dendritic cell-derived IL-12. Activation of T cells in the presence of IL-12 induces ligands for the endothelial selectins (3, 7, 28), allowing homing of effector T cells to the site of infection. Such activation may also maintain L-selectin expression on these T cells (11), thereby allowing them to continue to recirculate through lymph nodes in which Ag derived from the original insult would be reencountered. Consistent with this model, activation of T cells in the presence of IL-12 also leads to up-regulation of chemokine receptors involved in homing to cutaneous or other systemic sites (29, 30, 31). Therefore, we propose that IL-12 is the principal cytokine which directs the T cell immune and inflammatory response to skin-encountered pathogens.
The present report suggests that TGF-ß1 performs a parallel function
for the gut and gut-associated lymphoid tissue. Although quite distinct
immunologically, recruitment of leukocytes to the skin or the gut have
in common a high degree of dependence on selectins (3, 4).
Indeed, the thioglycollate peritonitis model is the best characterized
acute inflammatory model for its dependence on selectins. Furthermore,
TGF-ß1 induces on activated T cells integrins associated with gut
homing and retention
(4ß7 and
Eß7), and
down-regulates integrins associated with homing to skin and other sites
(LFA-1 and 4ß1; Refs.
12 and 13). Chemokine receptors specifically
associated with homing to the gut and gut-associated lymphoid tissue
have not been identified, but would also be predicted to be induced by
TGF-ß1. Therefore, activation of T cells in the presence of either
IL-12 or TGF-ß1 would have in common the property of inducing
functional ligands for the endothelial selectins, but would nonetheless
induce otherwise divergent homing pathways, consistent with the
specialized features of each site, and the requirement to segregate
these distinct responses. This tissue-specific orchestration of T cell
homing by IL-12 and TGF-ß1 is likely to be of considerable
significance for targeted and effective host defense.
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Acknowledgments |
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Footnotes |
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2 Current address: Department of Pathology, B263 Beckman Center, Stanford University School of Medicine, Stanford, CA 94305.
3 G.S.K. is an Established Investigator of the American Heart Association.
4 Address correspondence and reprint requests to Dr. Geoffrey S. Kansas, Department of Microbiology-Immunology, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611.
5 Abbreviations used in this paper: FucT-VII, (1,3)-fucosyltransferase VII; CHO, Chinese hamster ovary; CM, complete media; rh, recombinant human; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-related kinase.
Received for publication June 23, 2000. Accepted for publication August 9, 2000.
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(1,3) fucosyltransferase FucT-VII controls leukocyte trafficking through an essential role in L-, E-, and P-selectin ligand biosynthesis. Cell 86:643.[Medline]
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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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 T. de Vries, R. M.A. Knegtel, E. H. Holmes, and B. A. Macher Fucosyltransferases: structure/function studies Glycobiology, October 1, 2001; 11(10): 119R - 128R. [Abstract] [Full Text] [PDF]
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S. J. White, G. H. Underhill, M. H. Kaplan, and G. S. Kansas Cutting Edge: Differential Requirements for Stat4 in Expression of Glycosyltransferases Responsible for Selectin Ligand Formation in Th1 Cells J. Immunol., July 15, 2001; 167(2): 628 - 631. [Abstract] [Full Text] [PDF]
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) or absence (
) of 2
ng/ml TGF-ß1. Where indicated, cells were removed from culture and
analyzed by flow cytometry for staining with HECA-452. Data are
presented as percent HECA-452+ lymphocytes for each culture
condition at the indicated timepoint. Note different scale in
B. This figure represents one of four experiments.
A and B, Curves are significantly
different (p < 0.05) for all time points except
time zero.
