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Secretion by CD4+ T Cells in the Absence of TCR Ligation1
University of Montreal, Allergy Research Laboratory, Louis-Charles Simard Research Center, Notre-Dame Hospital, Montreal, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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. IFN- production
requires endogenous IL-12, the production of which in turn is dependent
upon CD40/CD154 interactions between CD4+ T cells and
monocytes. Indeed, non-TCR-activated CD4+ but not
CD8+ T cells express significant levels of CD154. IL-15 may
enhance IFN- in this system by up-regulating CD40 expression on
monocytes and IL-12Rß1 expression on CD4+ T cells.
Conversely, using neutralizing anti-IL-15 mAb, we show that the
ability of IL-12 to augment IFN- secretion is partly mediated by
endogenous IL-15. Finally, in the absence of monocytes, a synergistic
effect between exogenous IL-12 and IL-15 is necessary to induce IFN-
production by purified CD4+ T cells, while IL-15 alone
induces T cell proliferation. It is proposed that this codependence
between IL-12 and IL-15 for the activation of inflammatory T cells may
be involved in chronic inflammatory disorders that are dominated by a
Th1 response. In such a response, a self-perpetuating cycle of
inflammation is set forth, because IL-15-stimulated CD4+ T
cells may activate monocytes to release IL-12 that synergizes with
IL-15 to induce IL-12 response and IFN-
production. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-15 uses a heterotrimeric receptor composed of the ß- and
-chains of IL-2R and its own specific high-affinity binding
-chain (designated IL-15R) (1, 5, 6, 7). Since IL-15 binds and
signals through IL-2R subunits, this cytokine shares many biologic
activities with IL-2. IL-15 induces the proliferation of activated T
lymphocytes (1, 8) and costimulates with IL-12 the proliferation of NK
cells as well as their production of IFN-, granulocyte-macrophage
(GM)-CSF,4 and TNF- (9);
IL-15 also regulates NK cell survival (10) and induces
proliferation and Ig synthesis by human tonsillar B cells stimulated by
CD40 ligand or by B cell receptor engagement (11).
Interestingly, IL-15 is present at a low but significant level in the inflamed synovium of patients suffering from rheumatoid arthritis (RA), in which it displays potent T cell chemoattractant activity (12). The mechanisms of T lymphocyte activation in RA pathogenesis are not completely elucidated, and the triggering Ag is not yet identified (13).
We reported previously that IL-2 was capable of inducing IFN-
production by unfractionated non-TCR-activated T lymphocytes cocultured
with autologous monocytes (14). Because IL-15 shares many biologic
activities with IL-2, we examined whether IL-15 might substitute for
IL-2 in the activation of bystander T lymphocytes and play a role in
the maintenance of chronic inflammatory states. In the present report,
we show that IL-15 activates monocytes to release IL-12 upon contact
with CD4+ but not CD8+ T cells via a
CD40-dependent pathway. Conversely, IL-12-mediated IFN- secretion is
partly IL-15-dependent, inasmuch as IL-15 participates in IL-12
response and IFN- secretion.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human rIL-15 (Immunex, Seattle, WA) was used at 100 ng/ml. Human
rIL-2 (50 U/ml), human rIL-12 (60 pM), neutralizing Ab to IL-12 (goat
anti-human IL-12), and normal goat IgG Ab were kindly provided by
Dr. M. Gately (Hoffmann-La Roche, Nutley, NJ). Anti-IFN-
neutralizing mAb (clone p69) was provided by Dr. L. Garotta (Novartis,
Basel, Switzerland). Two anti-CD154 mAbs, clones M90 (mouse IgG1,
used for flow cytometry) and M92 (mouse IgG2a, used in culture), as
well as anti-IL-15 mAb, clone M110 (mouse IgG1), were generated by
Immunex. Isotype-matched control mAbs (mouse IgG1 and IgG2a) were
prepared in our laboratory.
Purification of adult mononuclear cells
Monocytes. PBMCs were isolated by density gradient centrifugation of heparinized blood from normal healthy volunteers using Lymphoprep (Nycomed, Oslo, Norway). Enriched monocytes (EMs) were prepared by cold aggregation as described previously (15), followed by one cycle of rosetting with S-(2-aminoethyl)isothiouronium bromide (Aldrich, Milwaukee, WI) -treated SRBCs to deplete residual T and NK cells. Monocyte purity was shown to be >95% by flow cytometry (FACScan, Becton Dickinson, Mountain View, CA) using phycoerythrin (PE)-conjugated anti-CD14 mAb (Ancell, London, Canada).
T lymphocytes. Enriched T cell populations were obtained from the monocyte-depleted PBMCs by rosetting with S-(2-aminoethyl) isothiouronium bromide-treated SRBCs and treating with ammonium chloride. Highly purified T cells were obtained following incubation for 20 min at 37°C with Lympho-kwik T (One Lambda, Los Angeles, CA). CD4+ T cells were isolated using Lympho-kwik TH (One Lambda), and CD8+ T cells were positively selected using anti-CD8-coated Dynabeads (Dynal, Oslo, Norway) followed by negative selection using anti-CD4-coated Dynabeads (Dynal) to remove double-positive cells (CD4+CD8+ T cells). T lymphocyte purity was assessed by flow cytometry (FACScan) using FITC-conjugated anti-CD3 mAb (Becton Dickinson), PE-conjugated anti-CD8 mAb, or FITC-conjugated anti-CD4 mAb (Ancell) and was shown to be >99% in all cases.
Culture conditions
Cultures were performed in serum-free HB101 medium (Irvine Scientific, Santa Ana, CA) supplemented with 2 mM glutamine, 1 mM sodium pyruvate, 10 mM HEPES, 100 IU penicillin, and 100 µg/ml streptomycin in the presence of polymyxin B (10 µg/ml) (Sigma, St. Louis, MO). T cells (106 cells/ml) were incubated with autologous monocytes (2 x 105 cells/ml) in flat-bottom 48-well Falcon plates (Becton Dickinson). Two-chamber cultures were performed in 24-well plates with Falcon cell culture inserts (Becton Dickinson). T cells (106 cells/ml) were added to the inserts in HB101 plus polymyxin B (10 µg/ml). Monocytes were added to the wells and supplemented with HB101 plus polymyxin B with or without T cells. When cultured alone, T cells were seeded at 106 cells/ml in RPMI 1640 medium containing 10% FCS and 2 mM glutamine, 100 IU penicillin, and 100 µg/ml streptomycin in the presence of polymyxin B.
Lymphokine determination
IFN- was measured by a sandwich solid-phase RIA using two
anti-IFN- mAbs as described previously (16). The detection limit
of the assay was 30 pg/ml. IL-12p40 and IL-12p75 were assessed by a
two-site sandwich ELISA using clone 2.4A1 or clone 20C2 as capture mAbs
and clone 4D6 as second mAb. Anti-IL-12 mAbs were generously provided
by Dr. M. Gately (Hoffman-La Roche). The sensitivity of the assays was
20 pg/ml and 6 pg/ml, respectively. IL-15 was measured by a sandwich
ELISA using mouse mAb to human IL-15 (clone M111) and polyclonal rabbit
anti-IL-15. The detection limit of the assay was 50 pg/ml.
Flow cytometric analysis
CD154 and IL-12Rß1 surface expression was assessed using a three-step procedure. Briefly, cells were first incubated with anti-CD154 mAb (clone M90), anti-IL-12Rß1 mAb (24E.6), or class-matched negative control mAbs at 5 to 10 µg/ml in the presence of normal human IgG (150 µg/ml) for 1 h at 4°C. Cells were then incubated with biotinylated goat anti-mouse IgG (Tago, Burlingame, CA) for 1 h at 4°C followed by PE-labeled streptavidin (Ancell). A two-step staining procedure was used to examine CD40 surface expression on monocytes. Cells were initially incubated with biotinylated anti-CD40 mAb (M89) or class-matched negative control mAb at 5 to 10 µg/ml in the presence of normal human IgG (150 µg/ml) for 1 h at 4°C followed by staining with PE-labeled streptavidin (Ancell). After staining, cells were analyzed using a FACScan (Becton Dickinson). Mean fluorescence intensity (MFI) was calculated as follows: (MFI specific mAb - MFI control mAb).
Thymidine incorporation
T cells were cultured for 5 days at 106 cells/ml in RPMI 1640/10% FCS containing polymyxin B (10 µg/ml) in flat-bottom Falcon 96-well plates (Becton Dickinson). DNA synthesis was assessed by adding 1 µCi/well of [methyl-3H]thymidine (10 Ci/mmol; Amersham, Arlington Heights, IL) during the last 6 h of the culture. Triplicate cultures were then harvested onto glass fiber filters, and the radioactivity was counted using liquid scintillation.
Statistical analysis
Results were analyzed by the paired Student t test using Instat software (GraphPad, San Diego, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by CD4+ T cells in the
absence of Ag largely depends upon their ability to promote IL-12
secretion by monocytes
In the present study, we first examined whether IL-15, a cytokine
that shares several biologic activities with IL-2, would substitute for
IL-2 in the induction of IFN- production by unstimulated T cells
cocultured with syngeneic monocytes. As shown in Figure 1
, unfractionated T cells secrete IFN-
when stimulated by IL-15 or IL-2 in the absence of Ag but in the
presence of monocytes. Anti-IL-12 Ab inhibits IFN- production by
70%, indicating that this response is largely IL-12-dependent. We
subsequently fractionated T cells into CD4+ and
CD8+ subpopulations (Fig. 2)
and demonstrated that only IL-15- or IL-2-stimulated CD4+
but not CD8+ T cells promote IL-12 secretion by monocytes
and secrete IFN-. IL-15 or IL-2 induce IFN- production by
CD4+ T cells in a dose-dependent manner. As shown in Table I, IL-15 or IL-2 induce both IL-12p40 and
p75 release in this coculture system. Of interest, IL-15 and IL-2
display an additive effect on both IFN- and IL-12 secretion (data
not shown). Finally, the results shown in Figure 2 also indicate that
purified monocytes stimulated by IL-15 or IL-2 do not secrete IL-12,
suggesting that IL-15 or IL-2-induced IL-12 production requires the
presence of CD4+ but not CD8+ T cells.
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secretion depends upon CD40-CD154
interaction
Next, we showed (Table II) that a
physical separation of CD4+ T cells and monocytes abolishes
IL-12 secretion, demonstrating that soluble factors produced by
IL-15-activated T cells are not sufficient to trigger IL-12 release.
However, the T cell-dependent IL-12 secretion is reduced by
neutralizing anti-IFN- mAb (Table II), suggesting that part
(30%) of the IFN- secretion produced via an IL-12-independent
pathway (Fig. 1
) could prime for enhanced IL-12 release in this
coculture system. Nevertheless, the IL-15-induced IFN- secretion
absolutely requires T cell contact with monocytes (Table II), which
favors the hypothesis that in addition to IL-12, other monokines may be
released upon contact with T cells and may contribute to IFN-
production. Given that CD40 ligation on monocytes is a well-described
mechanism to induce monokine release (including IL-12), we explored
this possibility and found that anti-CD154 mAb strongly inhibits
IL-12 release by monocytes and IFN- production by non-TCR-activated
CD4+ T cells (Table II).
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, A and B).
This low level of CD154 expression is not up-regulated by IL-15, by
IL-2, or by contact with monocytes (Fig. 3C and data not
shown). However, our data further showed that IL-15 or IL-2
significantly increases the expression of CD40 Ag on purified monocytes
(Fig. 3D). From these data, we propose that in the absence
of TCR-activated T cells, IL-15 may substitute for IL-2 in promoting
activation of bystander T cells. Indeed, IL-15 up-regulates CD40 on
monocytes that, following engagement by
CD154+CD4+ T cells, secrete IL-12 which may
synergize with IL-15 to induce IFN- secretion.
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secretion by CD4+ T cells
cocultured with monocytes is enhanced by endogenous IL-15
After having demonstrated that IL-15-induced IFN- production is
IL-12-dependent, we subsequently provided evidence that, conversely,
the ability of exogenous IL-12 to augment IFN- secretion is partly
IL-15-dependent in this coculture system. As depicted in Figure 4, neutralizing anti-IL-15 mAb
suppresses the IL-12-mediated IFN- production by CD4+ T
cells cocultured with monocytes by 63% (p =
0.002). In contrast, the IL-2-mediated IFN- secretion is
IL-15-independent. The specificity of the anti-IL-15 mAb is
demonstrated by the abolition of IL-15-induced IFN- in parallel
cultures. Since the above results using neutralizing mAb suggested that
endogenous IL-15 protein is involved in IL-12-induced IFN-
secretion, we examined whether exogenous IL-12 may increase IL-15
production. However, several experimental approaches attempting to
verify this hypothesis remained unsuccessful. We failed to detect IL-15
protein (as measured by a specific ELISA or by intracytoplasmic
staining) in T cell/monocyte cocultures as well as in IL-12-stimulated
PBMCs activated by LPS or Staphylococcus aureus Cowan
(data not shown), a culture condition that reportedly induces IL-15
secretion (17).
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response, we subsequently examined whether IL-15,
as reported for IL-2, may facilitate the IL-12 response by
up-regulating the IL-12Rß chain. The data in Figure 5 show that, regardless of the presence
of monocytes, IL-15 significantly augments IL-12Rß1 expression on
CD4+ T cells, strongly suggesting that IL-15 may increase
IL-12 responsiveness of purified T cells.
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production by
purified CD4+ T cells
Next, we explored the proliferative and IFN- response of
purified CD4+ T cells cultured in the absence of monocytes
to saturating doses of IL-15 used alone or in combination with optimal
concentrations of IL-12. Despite the expression of IL-12R (Fig. 5),
IL-15R (18), and IL-2R on purified CD4+ T cells, neither
IL-15, IL-2, nor IL-12 alone stimulate IFN- production; IL-15 and
IL-2 but not IL-12 induce significant T cell proliferation (Fig. 6). Most strikingly, IL-15 synergizes
with IL-12 to strongly induce IFN- secretion with no significant
increase in cell proliferation. Note that IL-2 may substitute for IL-15
in this synergy. Finally, although IL-15 promotes the response of
purified CD4+ T cells to IL-12, this IL-12-mediated IFN-
production is strongly increased upon contact with monocytes at day 3
(Fig. 7) or day 5 (data not shown), which
supports previous studies underlying the role of monocyte costimulatory
molecules in the response to IL-12. The data in Figure 7 also indicate
that a disruption of cellular contact between IL-15- plus
IL-2-stimulated T cells and monocytes completely abrogates IFN-
production, confirming that IL-12 production is not dispensable for
IFN- secretion by IL-15, IL-2, or IL-15 and by IL-2-stimulated
CD4+ T cells. Taken together, it is proposed that
IL-15-stimulated CD4+ T cells may proliferate and engage
CD40 on monocytes to promote IL-12 secretion; IL-15 and IL-12
synergize to induce a T cell IFN- response that is further amplified
upon contact with monocytes, providing a mechanism of activation of
inflammatory T cells in the absence of TCR triggering.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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by T
cells. Furthermore, the IL-12-mediated IFN- production by
non-TCR-activated CD4+ T cells in this coculture system is
partly IL-15-dependent. These data provide a potential mechanism of
inflammatory T cell activation in chronic disorders that are dominated
by a Th1 response, such as RA or sarcoidosis. Indeed, IL-15 is present
in significant quantities in the inflamed synovium of patients with
RA, which is in contrast to the relative absence of IL-2 (12).
Similarly, bronchoalveolar lavage cells from patients with sarcoidosis
express elevated levels of IL-12, IL-15, and IFN- mRNA (19, 20).
Previous studies indicated that synovial T cells costimulated by IL-15,
TNF-, and IL-6 induce TNF- production by monocytes, contributing
to the excessive TNF- observed in RA joints (21). Here, we show that
stimulation of CD4+ T cells by IL-15 alone is sufficient to
trigger IL-12 release by monocytes and to allow IFN- production. The
production of IL-12 in the IL-15-stimulated cocultures required a
CD40/CD154-dependent interaction between the T cells and the monocytes.
Thus, the ability of IL-15 to promote IL-12 in this system appears to
be indirect and may be due in part to its ability to up-regulate CD40
expression on the monocytes and enhance the production of IFN- by
CD4+ T cells. In that regard, we (22) and others (23) have
demonstrated previously that T cells activated through a TCR/CD3
complex induce IL-12 production by IFN- and GM-CSF-treated monocytes
via a CD40-dependent pathway. Indeed, IFN- and GM-CSF reportedly
up-regulate CD40 on monocytes (24). Our results show that unstimulated
CD4+ but not CD8+ T cells readily express CD154
at a sufficient level to engage CD40 on monocytes and to trigger
IL-12 release in the presence of IL-15, confirming and extending our
recent studies with IL-2-stimulated, unfractionated T cells (14) and
underlying the failure of CD8+ T cells to promote IL-12
secretion.
The failure of anti-IL-12 Ab to inhibit the IL-15-induced IFN-
secretion by >70% suggests that IL-12 may not be the only factor
involved in this response and is consistent with the ability of
neutralizing anti-IFN- mAb to reduce IL-15-induced IL-12 release
in this coculture system. Therefore, we propose that IL-15 or IL-2
contributes to the enhanced CD154/CD40 interactions at the early step
of the cultures leading to IL-12 (and possibly other monokines) and
IFN- production. The small amount of IFN- produced via an
IL-12-independent pathway will subsequently prime for increased IL-12
production and enhance CD40 expression, resulting in a further increase
in IFN- secretion and in the triggering of an amplification loop of
proinflammatory cytokine secretion. Recent data published during the
course of this study (25) showed that IL-15-induced IFN- by
anti-CD3 activated T cells largely depended upon APC-derived
endogenous IL-12, strongly supporting our present data.
Next, we provide evidence that IL-15 is involved not only in IL-12
production in the T cell/monocyte cocultures but is also required to
synergize with IL-12 to induce IFN- by the CD4+ T cells.
IL-15 increases the IL-12Rß1 chain on purified CD4+ T
cells and supports their IL-12-induced IFN- secretion. Wu et al.
(26) reported that IL-15 and IL-2 up-regulated the IL-12Rß chain on
PBMCs without defining the target cell subpopulations. Note that
purified, resting CD4+ T cells are unable to secrete
IFN- following IL-15 or IL-12 stimulation, while IL-12 reportedly
stimulates IFN- production by activated T and NK cells (27, 28). In
such a case, an optimal IL-12 response by T cells required the
expression of costimulatory molecules, including CD80, CD86, or CD58 on
APCs (29, 30, 31). In keeping with these studies, our data indicate that
IL-15 or IL-2 strongly synergizes with IL-12 to allow IFN-
production by resting, purified CD4+ T cells. While this
response is further enhanced upon contact with APCs, it does not
involve interactions between CD80, CD86, and their ligands (15). Of
interest, optimal concentrations of IL-15 induce T cell proliferation,
which is not further amplified by IL-12. In that regard, recent studies
by Kanegane et al. indicated that IL-15 increased
[3H]thymidine uptake of memory but not naive resting
CD4+ T cells (32).
Taken together, it appears that IL-15 may directly signal resting
CD4+ T cell proliferation but not IFN- production.
Kumaki et al. (33) reported that IL-15 down-regulated its own
high-affinity binding sites while up-regulating the IL-2R chain.
Since the IL-15R chain is required for high-affinity binding but not
for signaling by IL-15, and because IL-2Rß and IL-2R chains are
the limiting and determining factors for IL-15 responsiveness (6, 7, 8, 9),
our present data suggest that IL-15 signals through the IL-2Rß/
complex to induce resting CD4+ T cell proliferation.
In agreement with this hypothesis, Agostini et al. reported that IL-15
signaled through the IL-2Rß/ complex to trigger the growth of
CD4+ T cells in pulmonary sarcoidosis (20).
Ab neutralization demonstrated the involvement of monocyte-derived
endogenous IL-15 in IL-12-mediated IFN- production by
CD4+ T cells. In addition, exogenous IL-15 and IL-12
synergize to induce IFN- by purified CD4+ T cells. This
synergistic effect is reminiscent of studies on NK cell activation.
Indeed, IL-12 synergized with IL-15 or IL-2 to induce IFN- and
TNF- production by CD56dim NK cells (9); however, this
cytokine combination subsequently provoked apoptosis of the NK cells,
providing a mechanism of IFN- production down-regulation (34). It is
important to note that in the present report, purified T cells are
composed of >99% CD3+ cells, and that IL-12 plus IL-15-
or IL-2-stimulated monocyte preparations do not secrete IFN- (Ref.
35 and data not shown), largely excluding the possibility that IFN-
production derives from a few contaminating NK cells.
That CD8+ T cells cocultured with monocytes in the presence
of IL-15 or IL-2 do not produce IFN- likely results from their lack
of CD154 expression and from a subsequent absence of IL-12 release in
the cultures. However, this does not rule out the possibility that
CD8+ T cells may respond to exogenous IL-12. IL-15
reportedly triggers the activation and growth of the CD8+ T
cell pool in patients with HIV syndrome (36) and the proliferation of
memory and naive resting CD8+ T cells (32). Also, our
unpublished observations showed that IL-15 and IL-12 synergize to allow
IFN- production by purified CD8+ T cells.
Although IL-12-induced IFN- production is suppressed by neutralizing
anti-IL-15 mAb in the T cell/monocyte cocultures, we failed to
demonstrate that IL-12 up-regulates IL-15 protein by monocyte
preparations that were stimulated by bacterial Ag or left
unstimulated. In contrast to the wide expression of IL-15 mRNA
is the difficulty in documenting IL-15 protein in activated monocytes.
First, LPS-stimulated IL-15 and IL-12 production by monocytes occurred
after contact with NK cells (37). Second, endogenous IL-15 protein may
be up-regulated in blood-derived dendritic cells following phagocytosis
of immunomagnetic particles (38).
Taken together, the expression of IL-15 and IL-2 in different tissues
and cells suggests that they may be effective at different times and/or
different sites. As IL-2 is not produced by dendritic cells or
monocytes, IL-15 could be a substitute molecule used instead to trigger
and regulate the innate immune response. Upon bacterial or viral
infection, IL-15 may act as a chemoattractant for T cells (12, 39),
favor APC/T cell contact, and induce, in synergy with IL-12, IFN-
production by inflammatory T cells (as shown in our present study) or
by NK cells (9). As such, IL-15 could play a key role in the first line
of host defense mechanisms. In support of this possibility, IL-15 is
reportedly essential for activation of murine 
T cells during
early Salmonella infection at a time when they do not yet
produce IL-2 (40).
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Acknowledgments |
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Footnotes |
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2 Current address: Laboratory for Parasitic Diseases, Bldg. 4, National Institutes of Health, Bethesda, MD 20892-0425.
3 Address correspondence and reprint requests to Dr. M. Sarfati, University of Montreal, Allergy Research Laboratory (M4211-K), Louis-Charles Simard Research Center, Notre-Dame Hospital, 1560 Sherbrooke Street East, Montreal, Quebec, H2L 4 M1 Canada.
4 Abbreviations used in this paper: GM-CSF, granulocyte-macrophage CSF; RA, rheumatoid arthritis; PE, phycoerythrin; MFI, mean fluorescence intensity; EM, enriched monocyte.
Received for publication October 27, 1997. Accepted for publication June 3, 1998.
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 T. A. Fehniger and M. A. Caligiuri Interleukin 15: biology and relevance to human disease Blood, January 1, 2001; 97(1): 14 - 32. [Full Text] [PDF]
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M.-N. Avice, M. Rubio, M. Sergerie, G. Delespesse, and M. Sarfati CD47 Ligation Selectively Inhibits the Development of Human Naive T Cells into Th1 Effectors J. Immunol., October 15, 2000; 165(8): 4624 - 4631. [Abstract] [Full Text] [PDF]
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S. M. Santini, C. Lapenta, M. Logozzi, S. Parlato, M. Spada, T. Di Pucchio, and F. Belardelli Type I Interferon as a Powerful Adjuvant for Monocyte-derived Dendritic Cell Development and Activity In Vitro and in Hu-PBL-SCID Mice J. Exp. Med., May 15, 2000; 191(10): 1777 - 1788. [Abstract] [Full Text] [PDF]
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Z. Liu, K. Geboes, S. Colpaert, G. R. D'Haens, P. Rutgeerts, and J. L. Ceuppens IL-15 Is Highly Expressed in Inflammatory Bowel Disease and Regulates Local T Cell-Dependent Cytokine Production J. Immunol., April 1, 2000; 164(7): 3608 - 3615. [Abstract] [Full Text] [PDF]
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M. Ziolkowska, A. Koc, G. Luszczykiewicz, K. Ksiezopolska-Pietrzak, E. Klimczak, H. Chwalinska-Sadowska, and W. Maslinski High Levels of IL-17 in Rheumatoid Arthritis Patients: IL-15 Triggers In Vitro IL-17 Production Via Cyclosporin A-Sensitive Mechanism J. Immunol., March 1, 2000; 164(5): 2832 - 2838. [Abstract] [Full Text] [PDF]
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