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*
Unité de Recherche Associée 1461, Centre National de la Recherche Scientifique,
Pathology Department, and
Institut National de la Santé et de la Recherche Médicale, Unité 429, Hopital Necker-Enfants Malades, Faculté Necker, Université Paris-V René-Descartes, Paris, France; and
§
Institut National de la Santé et de la Recherche Médicale, Contrat Jeune Formation 95–01, Institut Curie, Section Recherche, Paris, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1, TGF-ß1 prevents the final LC maturation in
response to TNF-, IL-1, and LPS with respect to Class II CD80, CD86,
and CD83 Ag expression, loss of FITC-dextran uptake, production of
IL-12, and Ag presentation. In sharp contrast, CD40 ligand
cognate signal induces full maturation of LC and is not inhibited by
TGF-ß1. The presence of emigrated immature LCs in human reactive
skin-draining lymph nodes provides in vivo evidence that LC migration
and final maturation may be differentially regulated. Therefore, due to the effects of TGF-ß1, inflammatory stimuli may not be sufficient to induce full maturation of LC, thus avoiding potentially harmful immune responses. We conclude that TGF-ß1 appears to be responsible for both the acquisition of LC phenotype, cytokine production pattern, and prevention of noncognate maturation.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and
IL-1), and cognate CD4+ T cell help, mediated by CD40L (5, 7, 8). Recent studies showed that stimulation of CD8+ T
cells by DCs was achieved after a two step process: first, DCs were
induced to mature by Th cells via CD40/CD40L interaction or by viral
infection, and second, this so-called "licensed" DC may directly
stimulate cytotoxic T cells (3, 9, 10). At this time it is difficult, however, to reconcile the ability of DCs to mature in response to both the T cell-dependent signal (CD40L) and nonspecific stimuli with the specificity of the cognate immune response, which requires CD4+ T cell help for the response to most Ags. If inflammatory stimuli had the same effect as CD40L, LPS alone should be able to license DCs to activate killer T cells in vivo, bypassing the need for CD4+ help. Also, LC from mucosal barriers, which are frequently challenged with LPS and inflammatory signals, should be continuously activated and should stimulate CD4 helper as well as CD8 killer T cells in the absence of actual danger (11).
However, monocyte-derived DCs do not behave like LC. Indeed, while
TNF--induced maturation in GM-CSF + IL-4 monocyte-derived DC is
mediated exclusively via TNFRIp55 (6), only TNFRIIp75 mediates effects
of TNF- in human LC (12). The cytokine TGF-ß1, which is present in
the mucosal barriers, is required for differentiation of
epithelial-associated dendritic LC from their precursors, including the
monocyte (13, 14, 15, 16). We have previously shown that while GM-CSF- and
IL-4-treated monocytes give rise to non-Langerhans DCs, the addition of
TGF-ß1 allows monocytes to differentiate toward dendritic LC (15).
We show here that TGF-ß1, indeed, drastically changes the
requirements for DC maturation in this model. First, cells grown in the
presence of TGF-ß1 (LC) exhibit a more immature phenotype, lose
TNFRIp55 expression, and do not produce IL-10 after stimulation.
Second, and more important, TGF-ß1 inhibits LC maturation in response
to nonspecific signals such as LPS, TNF-, and IL-1, but not to the
cognate signal CD40L, while it does not inhibit down-regulation of
E-cadherin expression upon exposure to TNF- and IL-1. Furthermore,
we have observed immature LC in human reactive skin-draining lymph
nodes; this may reflect in vivo the relevance of our findings.
These results are consistent with the crucial role of CD40-mediated activation for the final maturation and licensing of DCs (3). By differentially regulating the differentiation, maturation, and functions of LC (and possibly of other DC subsets) in response to cognate T-dependent and nonspecific inflammatory signals, TGF-ß1 appears to be physiologically involved in the fine tuning of the immune response by DCs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The medium used was RPMI 1640 supplemented with 2 mM
L-glutamine, 100 U/ml penicillin, 100 mg/ml streptomycin,
and 10% heat-inactivated FCS Myoclone (all from Life Technologies,
Gaithersburg, MD), referred to below as complete medium. Recombinant
human GM-CSF was provided by Sandoz (Bale, Switzerland), recombinant
human IL-4 was purchased from Genzyme (Cambridge, MA), and recombinant
human TGF-ß1, TNF-, and IL-1ß were all purchased from R&D
Systems (Minneapolis, MN). LPS from Escherichia coli 0127-B8
and 026-B6 were purchased from Sigma Immunochemicals (St. Louis, MO).
Lysine-fixable FITC-dextran (Mr = 40,000) was
purchased from Molecular Probes (Eugene, OR). Murine fibroblast cell
lines transfected with human CD40L (LcCD40L) or CD32 (LcCD32) were
kindly provided by Dr. J. Banchereau and Dr. F. Brière
(Schering-Plough, Dardilly, France) (17). Tetanus toxoid was a kind
gift of Dr. F. Le Deist (Laboratoire d’Immunologie Clinique, Necker,
Paris, France). Anti-CD40 BB20-activating Ab (IgG1) was obtained from
Diaclone (Besançon, France). FITC-conjugated CD1a (clone BL1,
IgG1), MHC-I (MHC ABC, IgG2a), MHC-II (IgG2), CD83 (IgG2b), and
uncoupled CD80 (IgG1) and CD40 (IgG1) were obtained from Immunotech
(Marseille, France). Phycoerythrin (PE)-conjugated CD14 (Leu-M3,
IgG2b) and CD86 (IgG2b) were obtained respectively from Becton
Dickinson (Le Pont de Claix, France) and PharMingen (San Diego, CA).
Uncoupled anti-E-cadherin (HECD-1, mouse IgG1) was obtained from
R&D Systems. Lag Ab (mouse IgG1) was a kind gift of Dr F. Furukawa
(Hamamastu University, Hamdacho, Japan). CD120a (anti-TNFRIp55,
clone MR1–2) was obtained from Genzyme. Anti-DR (L-243, mouse IgG2a)
was obtained from the American Type Culture Collection (Manassas, VA).
Anti-lysosome-associated membrane protein-1 (LAMP-1) rabbit
antiserum was kindly provided by Dr. S. Carlsson, Umeå University,
Umeå, Sweden (18).
Culture of peripheral blood monocytes
DC and LC were prepared as previously described (15). Fresh CD14+ monocytes were isolated from PBMC of healthy volunteers obtained by the standard Ficoll-Paque method and immediately separated by negative magnetic depletion using hapten-conjugated CD3, CD7, CD19, CD45RA, CD56, and anti-IgE Abs (MACS; Miltenyi Biotec, Bergisch Gladbach, Germany) (19) and a magnetic cell separator (MACS) according to the manufacturer’s instructions, routinely resulting in >95% purity of CD14+ cells. Cells were cultured in flasks, or in 6- or 24-well tissue culture plates (Costar, Cambridge, MA) for 5 to 7 days in complete medium supplemented with 250 ng/ml GM-CSF and 100 ng/ml IL-4, resulting in their differentiation into CD1a+ DCs, or 250 ng/ml GM-CSF, 100 ng/ml IL-4, and 10 ng/ml TGF-ß1, resulting in their differentiation into CD1a+, E-cadherin+, cutaneous lymphocyte-associated Ag (CLA)+, Lag, and Birbeck+ dendritic LC. At days 2 and 4, fresh medium, supplemented with the above-mentioned cytokines, was added. FCS was absolutely required to obtain reproducibly homogeneous populations of CD1a+CD14-CD83-CD86- DC (but not LC) in the presence of GM-CSF and IL-4. However, we have determined, in a previous report (15), that concentration of TGF-ß1 found in FCS-supplemented medium was below 0.1 ng/ml, which is 100-fold less than required for acquisition of the LC phenotype by monocytes. The present study was done with a single FCS batch, but several differents batches were tested with the same efficiency to generate DC and LC.
Stimulation of DC and LC
DC and LC were collected at days 5–7 of culture, washed three
times in complete medium at 37°, and resuspended in 24-well tissue
culture plates at a concentration of 5 x 105 cell/ml
in complete medium supplemented with 250 ng/ml GM-CSF and 100 ng/ml
IL-4 with or without TGF-ß1 (10 ng/ml) for stimulation.
TNF-, IL-1ß, LPS, or medium alone was added at various doses for
40 h for stimulation with inflammatory cytokines and LPS. For
study of CD40L-mediated activation, fibroblastic L cells transfected
with either CD40L, or CD32 as control, were irradiated at 80 Gy and
added to the culture wells in a proportion of 1/10. Alternatively, DC
and LC were cocultured with fibroblastic L cells transfected with CD32
(Fc
RII) together with increasing concentrations of activating
anti-CD40 Abs. In all conditions, cells and supernatants were
collected after 40 h of activation. LC grown in the presence of
TGF-ß1 were either stimulated in the absence of TGF-ß1 (and
referred to as T-), or stimulated in the presence of TGF-ß1 (and
referred to as T+).
Flow cytometry analysis of PBMCs and PBMC-derived cells
For single- and two-color flow cytometry, 3 x 105 cells were incubated in 96-well plates (Becton Dickinson) for 15 min at 4°C in PBS, 2% human AB serum, and 0.01 M NaN3, mAbs at the appropriate concentration, or with control isotype-matched irrelevant mAbs at the same concentration. After washing, cells were incubated when appropriate with F(ab')2 goat anti-mouse (GAM)-FITC (Immunotech) for 15 min at 4°C in the same buffer, washed again, and then 104 events were analyzed with a FACScalibur (Becton Dickinson) using CellQuest software (Becton Dickinson).
Quantitation of endocytosis in single cell by FACS analysis
FITC-dextran uptake of DCs was assessed as previously described (6). Cells were resuspended in complete medium and incubated at 37°C with 5% CO2. FITC-dextran was added at a final concentration of 1 mg/ml. The cells were washed four times with cold PBS, 2% human AB serum, and 0.01 M NaN3 and were analyzed with a FACScalibur (Becton Dickinson) using CellQuest software (Becton Dickinson).
Confocal microscopy
Cells were adhered to glass slides coated with 50 µg/ml polyL-lysine (Sigma), fixed in 4% paraformaldehyde in Ca2+/Mg2+-free PBS, and quenched with 0.1 M glycine. Cells were permeabilized in PBS/saponin (0.01%)/gelatin (0.25%)/Nonidet P-40 (0.1%) and sequentially incubated with mAb L243 and anti-mouse FITC-conjugated secondary Abs, anti-LAMP-1 rabbit serum and TRITC-conjugated secondary Ab, or appropriate controls. Mounted slides were analyzed with a confocal laser microscope system attached to a microscope.
Quantitation of cytokine production by ELISA
Supernatants were stored at -70°C until cytokine measurements. Production of IL-10 and bioactive IL-12 p70 were measured in duplicate using ELISA Quantikine Kits (R&D Systems) according to the manufacturer’s instructions. Sensitivity of IL-10 and IL-12 detection was, respectively, 1.5 pg/ml and 0.5 pg/ml.
Autologous response to TT
DCs were collected, washed three times, pulsed for 48 h with TT or medium alone, with or without LPS (10 ng/ml) or LcCD40L. Cells were then washed two times in PBS, and half of the cells were fixed with 0.001% glutaraldehyde for 20 min on ice. Cells were washed again two times in PBS, resuspended in RPMI with 10% human AB serum, and added in triplicate at various concentrations to 105 autologous T cells/well in 96-well tissue cultue plates (Falcon, Oxnard, CA). T cells were isolated by the standard Ficoll-Paque method followed by magnetic depletion of non-T cells (MACS; Miltenyi Biotec). [3H]Thymidine (Amersham Life Science, Buckinghamshire, U.K.) incorporation was measured in newly synthesized DNA over 18 h, using pulses initiated at days 4 or 5 of the culture with 1 mCi/well of [3H]thymidine. Cells were then harvested with a 96-well Harvester (Pharmacia, St. Quentin, France) and collected on glass-fiber filters (Pharmacia); the incorporation of thymidine was measured with a ß-plate microscintillation counter (LKB, Pharmacia).
Immunohistochemistry
Serial cryostat sections of skin-draining reactive lymph node biopsies from three patients with dermatopathic lymphadenopathy were stained with CD1a, CD80, CD83, or CD86 mouse primary Abs and then labeled with a goat anti-mouse alkaline phosphatase-conjugated Ab. Double-stainings were performed using peroxidase and alkaline phosphatase-antialkaline phosphatase (APAAP) protocols according to published procedures (20, 21, 22). Fast Blue (Sigma) and 3 amino-9 ethylcarbazole (Sigma) were used as substrates for alkaline phosphatase and peroxidase, respectively.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As previously described by us, freshly isolated CD14+
monocytes from healthy donors differentiate toward
E-cadherin+, Lag+, CLA+,
Birbeck-granules+ LC in the presence of TGF-ß1, GM-CSF,
and IL-4, while, in the absence of TGF-ß1, they differentiate into
non-Langerhans monocyte-derived DCs (15). We further studied expression
of MHC Ags, costimulatory and activation molecules (CD80 and CD86,
CD83) by DC and LC. Flow-cytometry showed that, in comparison with DC,
LC expressed similar levels of membrane MHC class I but a 10-fold lower
level of membrane MHC class II Ags (Fig. 1
, c-f). LC also
exhibited a lower expression of CD80 than DC (Fig. 1, g and
h). CD83 and CD86 were negative (Fig. 1, i-l). TGF-ß1 thus induced down regulation of
membrane MHC II and CD80. Monocyte-derived LC stably retained this
immature phenotype in culture in the presence of TGF-ß1 from day 5 to
days 12–15, when cell death occurs.
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a, mature class II molecules
in DC were present on the cell surface and in an extensive cellular
compartment also containing LAMP-1, as previously described (6).
However, in LC derived from the same donors, in the presence of
TGF-ß1, MHC class II Ags were almost totally intracellular and mostly
colocalized with the LAMP lysosomal staining (yellow structures in Fig. 2, a and b). LC grown in the presence of TGF-ß1
thus exhibited features of early DC (23).
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It has been shown that LC in vivo do not express TNFRIp55 and do
not produce IL-10 (24, 25, 26, 27). We observed that the TNFRIp55 receptor
CD120a was also down-regulated on monocyte-derived LC to a low to
negative level, in comparison with DC (Fig. 1
, m and
n). Moreover, as shown in Fig. 3 (upper panel)
monocyte-derived LC, in contrast to monocyte-derived non-Langerhans DC
(p < 0.001), do not produce IL-10 after
stimulation with either LPS, TNF and IL-1 or CD40L.
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TGF-ß1 inhibits LPS, TNF-, and IL-1, but not CD40L-induced
maturation of LC
In addition to being necessary for in vivo and in vitro
differentiation of LC (13, 28), TGF-ß1 elicits diverse cellular
responses, including modulation of numerous immune and inflammatory
responses (29, 30). To investigate the effect of TGF-ß1 on DC
maturation, cells cultured for 6 days in the presence of GM-CSF and
IL-4 (DC) or in the presence of GM-CSF, IL-4, and TGF-ß1 (LC) were
collected, washed, cultured for 40 h in the presence of LPS,
TNF-, IL-1, both TNF- and IL-1, or murine fibroblasts transfected
with either human CD32 or CD40L and then analyzed for MHC II and
costimulation molecule expression by flow cytometry and confocal
microscopy, macropinocytosis activity, IL-12 production, and Ag
presentation.
TGF-ß1 inhibits LPS, TNF-, and IL-1, but not CD40L-induced
phenotypic maturation of LC.
Stimulation with 10 ng/ml of LPS, TNF-, IL-1, and both TNF- and
IL-1 induced up-regulation of class II Ags and CD86 on DC (cultured in
the absence of exogenous TGF-ß1) (Fig. 4) as previously described (5, 8).
However, strikingly, less than 20% of TGF-ß1-treated LC were induced
to up-regulate class II Ags and CD86 expression after a 40-h exposure
to 10 ng/ml LPS, TNF-, or IL-1, and only 25–40% of LC (vs 95% of
DC) were induced to mature even after exposure to 10 ng/ml
TNF- and 10 ng/ml IL-1ß in combination (Fig. 4).
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).
Similar results were obtained for CD83 (Fig. 5) and CD80 (not shown). Thus,
up-regulation of MHC II, costimulatory and activation-associated Ags is
differentially regulated in DC and LC, the latter appearing to be less
responsive to nonspecific signals. To further investigate this
phenomenon, we examined MHC II cellular location in stimulated cells by
confocal microscopy.
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and
IL-1 displayed nice dendritic cytoplasmic expansions and that mature
class II molecules were exclusively present on the cell surface, and no
longer in the LAMP-1+ lysosomal compartment (Fig. 2c). In contrast, in a large proportion of LC (>50%), MHC
class II Ags remained almost totally intracellular, while often not
colocalizing with the LAMP lysosomal staining (Fig. 2d),
thus resembling the intermediate DC phenotype (23).
Stimulation with CD40L, however, induced similar acquisition of the
dendritic-shaped morphology and class II expression at the cell surface
in both DC and LC (Fig. 2, e and f).
Dose response experiments (Fig. 5) further indicated that, while 
90%
of DC were induced to express CD86 and CD83 in response to LPS in a
dose-dependent manner, with a maximal effect for 1 ng/ml LPS, 90% of
LC stimulated in the presence of TGF-ß1 (LC T+) did not, even in
response to doses as high as 1 µg/ml LPS. Similarly, below
a concentration of 10 ng/ml of both TNF- and IL-1, only a very low
percentage of LC (<20%) was induced to mature, while 90% of DC
responded to much lower doses.
To investigate whether unresponsiveness of LC to inflammatory stimuli
was due to their stage of differentiation or to the presence of
TGF-ß1 during activation, cells were stimulated after retrieval of
TGF-ß1 (LC T-). When TGF-ß1 was withdrawn, the amounts of LPS
(Fig. 5, LC T-) and TNF- and IL-1 (Fig. 5, LC T-) needed to
activate LC were significantly lower, but remained at least 2 to 3 logs
higher than those required for DC maturation. Similar results were
obtained when 20 µg/ml of blocking anti-TGF-ß Ab (15) was added
to ensure the absence of active TGF-ß1.
For comparison, activation via CD40 was studied in a dose-dependent
manner by cocultivating day 6 DC and LC with CD32 (human
FcgRII)-transfected fibroblasts and increasing amounts of stimulating
anti-CD40 Ab for 40 h (Fig. 5). As expected, induction of CD83
and CD86 expression followed similar kinetics for DC and LC. Similar
results were obtained for MHC-II Ag expression, although they were
already expressed at a relatively high level on DC (Figs. 1 and 4).
Therefore, LC maturation in response to inflammatory stimuli was inhibited, and the presence of TGF-ß1 at the time of stimulation further increased the unresponsiveness of LC.
TGF-ß1 may also regulate maturation of DC generated in the absence of
exogenous TGF-ß1 in response to inflammatory cytokines. Addition of
TGF-ß1 at the time of stimulation partially inhibits up-regulation of
membrane class II and CD86 expression on DC, since 30–40% of DC
stimulated with 10 ng/ml of both TNF- and IL-1 remained
CD86- with intermediate level of surface class II Ags
(data not shown). However, maturation (i.e., up-regulation of membrane
class II and CD86 expression) of DC induced by 10 ng/ml LPS is not
inhibited by TGF-ß1, since 95% of LPS-stimulated DC became
DRhigh CD86high, whether or not TGF-ß1 (10
ng/ml) was added at the time of stimulation (data not shown).
Therefore, with respect to stimulation with LPS, TGF-ß1 might act
specifically on LC while it acts on both DC and LC with respect to
cytokines.
TNF- and IL-1 or LPS-treated LC maintain their pinocytic
activity in the presence of TGF-ß1.
Macropinocytosis activity was described to be correlated to the
immature stage of DCs (6). We thus investigated whether the apparent
absence of LC maturation after exposure to inflammatory stimuli
described above was associated with changes in their pinocytic
activity. As shown in Fig. 6, while
FITC-dextran intake was almost abolished in DC after exposure to LPS,
little or no change was detectable in LC, although basal FITC-dextran
intake is slightly lower than DC. Comparable results were obtained
after activation with TNF- and IL-1 (not shown), while
CD40L-stimulated DC and LC displayed a similar decrease of pinocytic
activity (Fig. 6).
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, and IL-1, but not CD40L.
Mature DCs produce IL-12, which plays a major role in cross-talk with
lymphocytes. We thus checked cytokine production of immature and
activated DC and LC, using ELISA, in culture supernatants after
nonspecific or CD40-mediated activation (Fig. 3, lower
panels). Activation with LPS (Fig. 3A) did not
reproducibly result in significant production of IL-12 by DC and never
resulted in the production of IL-12 by LC. When stimulated by either
TNF- and IL-1 (Fig. 3B) or CD40L (Fig. 3C), DC
produced significant levels of bioactive IL-12 p70. In contrast, while
CD40L-activated DC or LC produced identical amounts of IL-12 p70,
TNF- and IL-1-stimulated LC produced 50% less IL-12 than DC
(p < 0.05). This was reproducible in four
separate experiments, although levels of IL-12 production in response
to TNF- and IL-1 varied among donors. As it was observed for CD83
and CD86 Ag expression, retrieval of TGF-ß1 at the time of
stimulation partially restored IL-12 production by LC. Therefore, LC grown and stimulated in the presence of TGF-ß1 appeared to mature poorly in response to noncognate signals, while activation via CD40 appeared to induce similar maturation in comparison with DC.
Proliferative response to TT is dependent on LC activation via CD40L or T lymphocytes. Recent data showed that CD40L, which is mainly expressed by activated CD4+ helper T cells (31), provides the Th signal to induce the final maturation of DCs in vivo (3, 9, 10). We thus investigated the functional maturation of LC in response to inflammatory stimuli, CD40L, and Ag-specific T cells by using the autologous response to TT assays.
DC and LC pulsed with TT were able to stimulate autologous T cell
proliferative responses to TT in immune individuals. However, while
incubation of DC with LPS increased the Ag-specific proliferative
response, incubation of LC with LPS had no effect
(p < 0.05) (Fig. 7A).
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300 and identical to control cultures in which TT was omitted) (Fig. 7B). This indicated that LC have to mature before becoming
able to stimulate T cells and that LPS alone with TT was not able to
induce such maturation, while, in contrast, LC-Th cell crosstalk
induced LC maturation, resulting in T cell proliferation.
Indeed, pulsed LC stimulated with CD40L, either fixed or unfixed, give
rise to comparable proliferative responses (Fig. 7B),
indicating that CD40L is sufficient to induce maturation of LC.
Therefore, maturation of LC, necessary to induce a T cell proliferative response to TT, may be achieved by coculturing LC with either Ag-specific T cells, or with CD40L, but not by incubating them with LPS. This provides functional evidence to support our results analyzing class II Ags and activation marker expression, macropinocytosis activity, and IL-12 production.
In vivo and in vitro evidence that LC migration and maturation are independently regulated events
However, the maturation process of LC includes their migration
toward the draining lymph node (32). We thus investigated whether
migration of LC may occur before they fully mature in phenotype or
function. TNF- and IL-1 were demonstrated to contribute to LC
emigration from the epithelia (33), at least in part by reducing
membrane expression of E-cadherin (34, 35, 36). We thus investigated
regulation of E-cadherin expression on monocyte-derived LC. As shown in
Fig. 4, addition of 10 ng/ml of TNF- and IL-1 induced significant
down-regulation of E-cadherin expression on monocyte-derived LCs in the
presence of GM-CSF, IL-4, and TGF-ß1.
However, in vivo migration of LC does not rely only on E-cadherin
expression. We thus investigated the in vivo phenotype of LC that have
emigrated from the skin to the draining lymph node on three patients
with dermatopathic lymphadenopathy, a benign reactive condition in
which skin-draining lymph nodes are enlarged, due to the accumulation
of LC in T cell zones. In three of three patients, immunohistochemical
staining on serial sections showed that a large number of cells in the
T cell zones expressed high levels of CD1a and are thus poorly mature
LC; most of these cells did not express detectable levels of CD83,
CD86, and CD80. A double immunostaining using CD1a and CD83 Abs is
shown in Fig. 8;
CD1a+CD83low/- are numerous in the
T cell zone (closed arrowhead), while some
CD1a+CD83+ cells are also present (arrow).
CD1a-CD83+ (open arrowhead) cells are mainly
found in the B cell follicle (F). This result suggests that
phenotypically immature LCs can migrate into the draining lymph node in
response to an inflammatory signal.
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and IL-1. Rather, our results suggest that TGF-ß1 prevents
the functional maturation of these cells unless a cognate signal such
as CD40L is provided. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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These results further indicate that monocyte-derived LC behave as do in
vivo LC in many aspects. Indeed, it has been shown that in vivo LC only
express TNFRIIp75 (24) and respond to TNF- via TNFRIIp75 and not
TNFRIp55 (12) while, in contrast, monocyte-derived DC respond to
TNF- by TNFRIp55 and not TNFRIIp75 (6). Also, in vivo LC and in
vitro CD34+-derived LC do not produce IL-10 (25, 26, 27), while
dermal CD11b+ macrophages/DCs in vivo (25, 26), in vitro
CD34-derived (27), and monocyte-derived non-Langerhans DC produce IL-10
upon stimulation. These findings distinguish LC from dermal DC, which
resemble more closely the monocyte-derived DCs generated in the
presence of GM-CSF and IL-4 without exogenous TGF-ß1, while the two
DC subsets (dermal DC and LC) may be closely related (37).
More important, the present study also shows that maturation of LC is
differentially regulated by TGF-ß1: 1) TGF-ß1 allows
down-regulation of E-cadherin expression by the whole LC population in
response to TNF- and IL-1 but inhibits LC maturation after exposure
to LPS, TNF, and IL-1, with respect to Class II, CD80, CD86, and CD83
Ag expression, loss of FITC-dextran uptake, production of IL-12, and Ag
presentation; 2) in contrast, cognate T cell-dependent stimuli (i.e.,
CD40-mediated) induce full maturation of LC and are not influenced by
TGF-ß1; 3) in vivo maturation (i.e., induction of CD80, CD86, and
CD83 Ag expression) does not necessarily precede migration, and, in
accordance, it has been shown that LC do not need to be fully mature in
phenotype or function before they leave the skin (32).
These results are consistent with the crucial role of CD40-mediated
activation for the final maturation and "licensing" of DCs (3, 9, 10). LC are the DCs of the epithelial barriers, including the skin and
oral, nasal, esophagal, pulmonary, vaginal, and rectal mucosae. These
cells are thus challenged frequently with numerous pathogens and
traumatic events and reside in epithelia where TNF- and IL-1 are
produced at relatively high levels (28). LC represent the main
population of APC in the mucosal barriers, and the main source of IL-12
after stimulation, but do not produce IL-10 and drive Th1 responses
such as delayed-contact hypersensitivity. It would be dangerous for the
host if inflammatory stimuli were able to "license" LC in a way
that enable them to stimulate an effector response. Our results
indicate that TGF-ß1 may be responsible for the cognate T cell
dependence of LC maturation. By dampering the effect of inflammatory
cytokines and LPS on the functional maturation of LC, TGF-ß1 may
prevent the noncognate maturation of LC via bystander inflammatory
cytokines present in epithelia, thereby avoiding potentially harmful
immune responses.
After Ag exposure, TNF- and IL-1 contribute to LC emigration from
the epithelia (33, 34), at least in part by reducing membrane
expression of E-cadherin (35, 36). Our results are in accordance with
these data; however, we propose that these stimuli are not sufficient
to induce final maturation of DC, due to the presence of TGF-ß1. Once
in lymphoid organs, LC interact with naive Ag-specific helper T cells.
This contact, which may be facilitated by attracting chemokines, can be
sustained for 20 h in certain circumstances (38). If cognate
recognition occurs, this crosstalk may lead to activation of both the
helper T cell and the LC, thus initiating a helper CD4+
immune response and "licensing" mature LC (so-called
interdigitating DCs) to stimulate cytotoxic T cells (3). It could be
tempting to further speculate that this crosstalk in the T cell area of
lymph nodes may also result in tolerance.
Uncontrolled maturation of LC by nonspecific bystander signals and
consecutive inappropriate T cell activation might break tolerance.
However, DCs grown in the absence of TGF-ß1, which may correspond to
dermal (39) and some nonmucosal DCs, become mature in response to
cytokines or LPS and produce IL-10. These cells have been proposed to
mediate humoral rather than cellular immune responses (40). In
addition, LPS or TNF-, away from the periphery, e.g. in the spleen,
represent "danger" (e.g., septicemia). Conversely, production of
TGF-ß1 by tumoral cells may locally hamper inflammatory-induced
maturation of DC and reduce antitumoral immune responses.
We have shown here that several DC activation pathways may be
inhibited by TGF-ß1, while another (i.e., CD40L) remains unaffected.
Although a common ceramide-mediated signaling pathway was described for
CD40L, TNF-, and IL-1 in DC (41), it is clearly not affected in
TGF-ß1-treated LC, since CD40L-induced activation and Ag presentation
are not inhibited. CD14, the main known LPS receptor, was barely
detectable in both DC and LC (15). We have shown in this study that
TGF-ß1 down-regulates membrane TNFRIp55 on LC vs DC. However,
stimulation via CD40 induces IL-12 production in both DC and LC at
similar levels, but LC do not produce IL-10, while DC produce large
amounts of this cytokine. Therefore, differential regulation of
receptor expression is not the only mechanism involved in the
alternative responses to external stimuli by DC and LC. CD40 may engage
different downstream signaling molecules in the two cell types.
In conclusion, TGF-ß1 appears to be a major cytokine in DC biology, responsible for the acquisition of the LC phenotype and the prevention of noncognate maturation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. F. Geissmann, URA CNRS 1461, Hopital Necker-Enfants Malades, 161 rue de Sevres, 75743 Paris Cedex 15, France. E-mail address:
3 Abbreviations used in this paper: DC, dendritic cell; LC, Langerhans cell; CD40L, ligand for CD40; TRITC, tetraethylrhodamine isothiocyanate; TT, tetanus toxin; CLA, cutaneous lymphocyte-associated Ag; LAMP, lysosome-associated membrane protein.
Received for publication October 23, 1998. Accepted for publication January 20, 1999.
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