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Laboratory of Immunology, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain
(IL-4R-/-) retain the capacity to secrete IL-4 and can
be used to identify those cell types that produce IL-4 without a
requirement for prior IL-4-mediated stimulation. To address whether
naive, conventional CD4+ T cells may act as initial
producers of IL-4 in Ag-specific responses, we crossed the BALB/c
IL-4R-/-mice to DO11.10/scid TCR
transgenic mice. Lymph node cells from wild-type and
IL-4R-/- DO11.10/scid mice secreted
50 pg of IL-4 per106 cells within 48 h after
peptide stimulation. This small amount of IL-4 was sufficient to cause
the differentiation of wild-type CD4+ T cells into Th2
cells, particularly if IFN-
and IL-12 were neutralized during the
priming cultures. CD4+ cells from the
IL-4R-/- mice gave rise to a minor proportion (2%)
of IL-4-producing cells upon stimulation in the presence of
anti-IFN- and anti-IL-12. These data show that conventional,
naive CD4+ T cells may be considered as initial sources of
IL-4 and, in the absence of IFN- and IL-12, this IL-4 can induce Th2
polarization. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/
T cells (15), and
conventional CD4+ T cells
(16, 17, 18, 19, 20, 21, 22). Conventional T cells, either those that have been previously primed or naive cells, are attractive candidates as a source of the "early" IL-4 because they are in the "right place at the right time." Whether such cells could be prime movers has been uncertain because their acquisition of the ability to produce IL-4 has generally been regarded as an IL-4-dependent event. However, it has been suggested that naive T cells may make small amounts of IL-4 (or rare naive T cells may make large amounts) simply in response to TCR/CD28-mediated stimuli. To establish this, one needs to use highly purified populations of naive, conventional CD4+ T cells and be assured that these cells have not previously received an IL-4 receptor-mediated signal.
Previous groups have made efforts to establish the capacity of naive T cells to produce the early IL-4 needed for priming. In general, they have used cells with high buoyant density that were sorted for expression of high levels of CD62L or CD45RB and/or low levels of CD44. In some cases, this has been done in mice that were TCR transgenic. These studies generally measured the capacity of these cells to become IL-4 producers in the absence of added IL-4 and concluded that, depending on the concentration of Ag and the degree of costimulation, Th2 priming could be achieved (18, 19, 22). In some experiments, it was shown that such priming was blocked by anti-IL-4.
These studies, although arguing that naive cells can be the source of
IL-4, do not conclusively establish this point. Most importantly, the
cells were drawn from mice that can both make and respond to IL-4 so
that such cells could have received an IL-4 signal in vivo and
differentiated into Th2 cells and then returned to the resting state.
Such cells would then be able to make IL-4 upon restimulation. Indeed,
because the TCR transgenic mice used were not on
scid or RAG backgrounds, their expression of alternative TCR
-chains makes environmental immunization possible. Furthermore, it
is now clear that CD62L is not a reliable marker of the naive state
because memory cells can revert to being CD62L bright
(23).
We have readdressed this important issue using mice in which the
IL-4R-chain has been disrupted, crossed to TCR transgenic mice on a
scid background, and have further used IL-4xIL-4R
double-knockout (KO) cells as APC. The possibility of / or NK T
cells as a source of IL-4 is eliminated in this system because neither
cell type is present in these mice. Neither basophils/mast cells nor
eosinophils are likely to be involved because few, if any, of these
cells are found in lymph nodes (LNs), which were our source of T cells.
Finally, because we use APCs from IL-4xIL-4R donors, the APC can
neither produce nor consume IL-4. This makes a source of IL-4 other
than the naive T cells most unlikely and also allows us to quantitate
IL-4 production because depletion of IL-4 from culture medium by
receptor-mediated endocytosis should be largely eliminated. This system
allows an unambiguous measure of the early production of IL-4 by
conventional, naive T cells and a determination of whether this IL-4 is
sufficient to prime naive IL-4R+ cells to
become Th2 cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c IL-4-/- and
IL-4R-/- mice were generated as described
(24, 25) and bred under specific pathogen-free conditions
in the National Institute of Allergy and Infectious Diseases Animal
Care Unit. DO11.10/scid TCR mice (26) were
crossed to the IL-4R-/- mice and screened by
FACS for the TCR clonotype KJ1-26 (Caltag, South San Francisco, CA) and
CD45R/B220 (PharMingen, San Diego, CA) expression on PBLs and for the
presence of the mutated IL-4R locus by PCR. 5CC7xRAG2
TCR (27) mice and IL-4-/- mice on
a B10.A background were bred at Taconic Farms (Germantown, NY). The
BALB/c nude mouse strain (nu/nu) was purchased from the
Division of Cancer Treatment, National Cancer Institute
(Frederick, MD).
Culture medium
Complete RPMI (cRPMI) consisted of RPMI 1640 medium (Biofluids, Rockville, MD) supplemented with 10% FBS (Life Technologies, Rockville, MD), 1 mM sodium pyruvate, 2 mM L-glutamine, 0.05 mM 2-ME, 100 U/ml penicillin, and 100 µg/ml streptomycin.
Abs and cytokines
CD4-CyChrome, IL-4-PE, IFN--FITC, Vß8-FITC, anti-CD3,
and anti-IL-3 were all purchased from PharMingen. Human IL-2 was a
gift from Perkin-Elmer/Cetus (Norwalk, CT). Anti-IL-4 (11B11),
anti-IL-12 (C17.8), anti-IFN- (XMG 1.2), and anti-mouse
Fc receptor (2.4G2) mAbs were all purified from ascites by Harlan
Biosciences (Madison, WI). Anti-mouse IL-4R (M1) was purchased from
Genzyme (Cambridge, MA). Goat anti-mouse IgD plasma was a generous
gift from Fred Finkelman (University of Cincinnati, OH). Mouse IL-4 was
obtained from a recombinant baculovirus prepared by Cynthia Watson
(Laboratory of Immunology, National Institute of Allergy and Infectious
Diseases). Recombinant mouse IL-3 was purchased from Genzyme. For T
cell depletions, spleen cells were incubated with 20% supernatants of
anti-Thy-1.2 mAb HO13.4 and rabbit complement (Cedarlane
Laboratories, Hornby, Ontario, Canada).
ELISAs
IL-4 (Endogen, Woburn, MA) and IL-2 (PharMingen) ELISAs were performed according to manufacturer directions. For the serum IgE ELISA, 96-well plates were coated with 2 µg/ml each of two monoclonal anti-IgE Abs (02131D from PharMingen and AMI2501 from BioSource, Camarillo, CA). After blocking and overnight incubation with serum samples, plates were developed with HRP-conjugated goat anti-IgE Abs (Southern Biotechnology Associates, Birmingham, AL) followed by peroxidase substrate (Bio-Rad, Hercules, CA). The mAb IgE standard (D-8406) was purchased from Sigma BioSciences.
In Vitro priming
Mesenteric LN cells (1 x 106/ml)
from DO11.10/scid IL-4R+/- and
IL-4R-/- mice were cultured in 24-well
plates in cRPMI and IL-2 (10 U/ml) and stimulated with 3 µM OVA
peptide and T-depleted irradiated spleen cells (5 x
106/ml) from BALB/c IL-4xIL-4R
double-deficient mice as APC. The peptides for OVA (323–339) and
pigeon cytochrome c (88–104) were purchased through
National Institute of Allergy and Infectious Diseases, Laboratory of
Molecular Structure-Peptide Synthesis Laboratory. Some cultures also
contained anti-IFN- (10 µg/ml) and anti-IL-12 (10
µg/ml), IL-4 (1000 U/ml), or anti-IL-4 (20 µg/ml). On the
second or third day of culture, the cells were diluted 1:5 in cRPMI
with IL-2 and expanded into 6-well plates. Five to six days after the
initial stimulation, cells were harvested, washed twice, and replated
at 1 x 106/ml in cRPMI with IL-2 and
challenged for an additional 5-day priming under the same conditions.
LN cells from 5CC7xRAG2 TCR transgenics were primed similarly, but
with 3 µM PCC peptide and T-depleted irradiated spleen cells (5
x 106/ml) from B10.A
IL-4-/- mice as APC.
Intracellular cytokine staining
In vitro primed cells were harvested, washed, and cultured at
1 x 106/ml in cRPMI in 48-well plates with
3 µM OVA peptide, 3 µM monensin (PharMingen), and 5 x
106/ml T-depleted irradiated spleen cells from
BALB/c (IL-4xIL-4R)-/- mice as APC. After
6 h, cells were washed, fixed in 4% paraformaldehyde, and
permeabilized with 0.1% saponin in PBS containing 1% FCS. Cells were
first blocked with 2.4G2 (10 µg/ml) then stained simultaneously with
CyChrome-anti-CD4, FITC-anti-IFN-, and PE-anti-IL-4 (all
obtained from PharMingen) and analyzed by FACS. For the 5CC7xRAG2
culture, cells were stimulated with 3 µM PCC peptide, 3 µM
monensin, and T-depleted irradiated spleen cells (5 x
106/ml) from B10.A
IL-4-/- mice.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- mice produce an
early burst of IL-4
To address whether naive conventional CD4+ T
cells are capable of producing an initial burst of IL-4 upon TCR, we
crossed DO11.10 TCR transgenic mice on a homozygous scid
background to the BALB/c IL-4R-/- mutants.
Such mice would lack NK T cells, and the scid mutation would
guarantee exclusive expression of the appropriate transgenic TCR. To
further exclude IL-4 production from the splenic APC population and
consumption of the IL-4 produced in the cultures, we used irradiated
T-depleted spleen cells from
(IL-4xIL-4R)-/- double-deficient mice
as APC.
LN cells from DO11.10/scid
IL-4R+/- and
IL-4Ra-/- mice were cultured with 3 µM OVA
peptide, and supernatants were obtained at 48 h (Fig. 1
). Such supernatants contained 50
pg/106 cells/ml of IL-4. We failed to detect any
IL-4 when IL-4R+/- cells were cultured with
peptide alone. However, the addition of anti-IL-4R mAb resulted
in the appearance of a comparable amount of IL-4 in supernatants from
such cells, arguing that the "early" IL-4 was rapidly consumed by
the CD4+ T cells. Thus, both
IL-4R+/- and
IL-4R-/- DO11.10 cells respond to OVA,
resulting in the production of 50 pg of IL-4 per million cells within
48 h.
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To assess whether the small amount of IL-4 produced within 48
h after stimulation was capable of generating a Th2 response, LN cells
from DO11/10/scid/IL-4R+/- and
IL-4R-/- mice were stimulated for a 5-day
priming period with OVA peptide in the presence of irradiated
T-depleted spleen cells from IL-4xIL-4R-/-
donors. Amounts of IL-4 in the supernatants and the frequency of
IL-4-producing cells were measured after restimulation with peptide and
APCs (Fig. 2 and Table I).
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, "peptide alone") and the amounts of
supernatant IL-4 were low (Table I). The addition of IL-4 to the
IL-4R+/- cells dramatically increased the
frequency of IL-4-producing cells and the amount of supernatant IL-4.
As expected, no change was seen in the
IL-4R-/- cells cultured with IL-4.
If IL-4R+/- cells were cultured without added
IL-4 but in the presence of anti-IFN- and anti-IL-12, 4% of
the cells produced IL-4, and supernatant IL-4 content was 4823
pg/106 cells. When anti-IL-4 Ab was added to
such cultures, the number of IL-4-secreting cells fell to 1.7%, and
the amount of supernatant IL-4 was reduced to 1121
pg/106 cells. This argues that the endogenous
production of IL-4 by IL-4R+/- cells was
sufficient to cause the induction of a modest number (3%) of
IL-4-producing cells but only if IFN- and IL-12 were
neutralized.
The data also show that there is a small number IL-4-producers even in
the absence of stimulation through the IL-4 receptor. The latter
conclusion is supported by results with the
IL-4R-/- cells primed in the presence of
anti-IFN- and anti-IL-12, with or without IL-4 or
anti-IL-4. In these cultures, supernatant IL-4 levels ranged from
386–646 pg/106 cells, slightly less than that
obtained in the IL-4R+/- cells cultured with
anti-IFN-, anti-IL-12, and anti-IL-4 (1121
pg/106 cells) (Table I).
These results lead us to conclude that the modest amount of IL-4
produced by DO11/10/scid/IL-4R+/-
and -/- CD4+ T cells in
response to Ag stimulation is sufficient to polarize a small proportion
of the responding cells (i.e., the IL-4R+/-
cells) when IFN- and IL-12 are neutralized.
When these cells were recultured for five additional days under the
same conditions, they proved to be excellent IL-4-producers when
challenged; 29.3% produced IL-4 (Fig. 2B), and supernatant
IL-4 content was 157,000 pg/106 cells (Table I).
Only 4.2% of the cells primed in the presence of anti-IL-4,
anti-IL-12, and anti-IFN- produced IL-4 after the second
round of priming. This strongly implies that the enhanced IL-4
production observed after the second round of stimulation is in
response to endogenously produced IL-4, and not simply due to
repetitive stimulation.
In contrast to the wild-type (WT) cells, the twice-primed
IL-4R-/- cells had a frequency of
IL-4-secreting cells ranging from 2.2–3.0%, and the amount of
supernatant IL-4 ranged from 1600–2140 pg/106
cells in the cultures containing anti-IFN- and anti-IL-12.
The latter provides a more rigorous reflection of the IL-4-independent
component of the polarization process than the result obtained with
heterozygous cells.
Because these cells are derived from BALB/c mice, the possibility
remained that the IL-4 response we observed was peculiar to this mouse
strain, which has been reported to "default" to Th2 cells upon
priming in the absence of added IL-4 (28). To address
this, we performed a similar experiment with cells from 5CC7xRAG2 TCR
transgenic mice, which are on a B10.A background. These cells were
primed with 3 µM PCC peptide. As shown in Fig. 2, the 5CC7 cells
showed trends in IL-4 production comparable to the BALB/c
IL-4R+/- mice. More importantly, a small
percentage of IL-4 producers were detected after the first round of
priming with pigeon cytochrome c peptide in the presence of
anti-IFN- and anti-IL-12. This was strikingly augmented
after the second priming. This further confirms that vigorous Th2
responses develop similarly in CD4+ T cells from
BALB/c and B10.A backgrounds, particularly when IFN- and IL-12 are
neutralized.
Thus, in the absence of exogenous IL-4, a limited amount of IL-4 is
produced by naive cell populations; such production is sufficient so
that a substantial degree of polarization can be achieved through
repetitive culture. Endogenously produced IFN- and IL-12 will block
this effect, presumably by limiting the responsiveness of the T cells
to the very modest amounts of IL-4 produced early in the first
culture.
IL-4 has been shown to enhance survival of T and B cells (as reviewed
in Ref. 29). To exclude the possibility that the increase
in IL-4-production in the IL-4R+/- cell
population compares to IL-4R-/- cells
reflects preferential survival of the IL-4R-expressing cells, we
measured the total number of live cells recovered after each round of
priming. There was no appreciable difference in either
IL-4R+/- or -/-
groups cultured with or without IL-4 (Table II). This makes it quite unlikely that
the enhanced differentiation of IL-4R+/-
cells into IL-4 producers can be accounted for by a proliferation
mechanism.
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-/- miceOur results indicate that naive CD4+ T cells secrete an early burst of IL-4 that is capable of driving Th2 responses in vitro. We next asked whether such IL-4R-independent IL-4 production is functionally active during an in vivo response. A potent stimulus of IL-4 production and of IgE responses is treatment of mice with goat Ab to mouse IgD (30). Although the stimulus is specific for B-cells, Ag-specific CD4+ T cells (30) are required to induce the response. It has also been shown that NK T cells do not contribute to IL-4 production because CD1-/- mice that are deficient for NK T cells retain IL-4-dependent IgE responses after anti-IgD treatment (31).
To determine whether the capacity of T cells to produce IL-4 in
response to anti-IgD required prior priming through the IL-4
receptor, WT and IL-4R-/- mice were treated
with anti-IgD. As shown in Fig. 3A, the frequency of cells
with cytosolic IL-4 in response to anti-IgD was comparable between
the heterozygous controls and IL-4R-/- mice.
Nearly all IL-4 producers were in the CD4+ T cell
population. In addition, using quantitative, competitive RT-PCR, the
number of IL-4 transcripts in total spleen cells from anti-IgD
treated IL-4R-/- mice was actually 2-fold
greater than that of WT mice (data not shown).
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-/- mice that are
Vß8+ is 21% (1.5 of 7.2% total IL-4
producers), which is only slightly greater than the frequency of
Vß8+ cells that did not produce IL-4 (13.5%)
(Fig. 3B). NK T cells have been shown to have a frequency of
Vß8+ cells of 55%. Thus, it seems likely
that conventional CD4+ T cells can be stimulated
by anti-IgD to produce IL-4 even if these cells are incapable of
responding to IL-4.
Because the capacity of conventional CD4+ T cells
from IL-4R-/- mice to produce IL-4 in
response to anti-IgD injection, we next asked whether this IL-4 was
functionally capable of stimulating B cell Ig class switching to IgE,
which is generally an IL-4-dependent event. We transferred WT spleen
cells from BALB/c nu/nu mice to
IL-4R-/- recipients and asked whether
anti-IgD could induce IgE expression in the reconstituted animals.
As shown in Fig. 4, anti-IgD-treated
IL-4R-/- mice had very low levels of IgE,
but when reconstituted with nu/nu spleen cells, they
developed IgE levels of 60.4 µg/ml, equivalent to the response of
intact BALB/c mice. It is interesting to note that even without the
addition of WT spleen cells, IgE was modestly increased in the
IL-4R-/- mice after anti-IgD treatment
(undetectable to 308 ng/ml). IL-4-independent IgE production has been
observed in other systems; in IL-4 and IL-4R KOs, IgE production of
0.1–1% of normal is often observed (32). Thus,
anti-IgD injection induced IL-4R-independent IL-4 production by
a cell population that can mediate Ig class switching, further
supporting the notion that these are "conventional"
CD4+ T cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- T cells. Cells from IL-4R mutant
mice provide a unique opportunity to measure such early IL-4 production
because IL-4 is not consumed by these cells, nor can IL-4-dependent,
IL-4-producing cells appear in the culture. Furthermore, the absence of
IL-4R assures that there is no possibility that these cells would be
previously exposed to IL-4 in vivo and therefore "primed", either
by IL-4 produced by endogenously activated CD4+
cells or by non-T cell sources of IL-4 such as mast cells.
We examined Ag-specific IL-4 production by LN cells obtained from
D011.10/scid mice that were either mutant or wild type at
the IL-4R locus. Under these conditions, 50 pg/ml were
produced by 106 cells. This is an amount that is
less than that required to optimally polarize naive
CD4+ T cells to become Th2 cells (generally
500-1000 pg/ml) but may still be sufficient to cause a degree of
polarization.
Therefore, we asked whether T cells from WT DO11.10/scid
mice could use their endogenously secreted IL-4 to differentiate into
Th2 cells. Our data demonstrate that LN cells from
DO.11.10/scid mice stimulated with 3 µM OVA peptide prime
for IL-4 production when IFN- and IL-12 were neutralized. Under
these conditions, 4% of the T cells became IL-4 producers. When
stimulated through a second round, this rose to 30%, presumably due to
the substantial amounts of IL-4 produced in the first round. Thus the
early IL-4 secreted by naive T cells appears to be sufficient to prime
for a delayed, but eventually quite striking, Th2 response, if IL-12
and IFN- are neutralized.
These experiments also show that a small percentage of transgenic
CD4+ T cells from
IL-4R-/- mice can acquire IL-4-producing
capacity when primed in the absence of IFN- and IL-12. Whether this
represents IL-4-independent in vitro priming or the response of cells
that were actually primed in vivo is not certain. The latter is
rendered unlikely by the fact that the cells used were derived from
mice on a scid background, which should be much less likely
to be primed by environmental Ags.
Our results demonstrate that there is an IL-4-independent in vivo
pathway of IL-4 secretion by "conventional" T cells. Injection of
anti-IgD into IL-4R mutant mice resulted in the same frequency
of IL-4-producing CD4 T cells as in WT mice (Fig. 3). Although Kaplan
et al. have reported that that IL-4-secreting cells in
STAT6-/- mice express the NK Ag DX5, it is most
unlikely that the cells making IL-4 in response to anti-IgD are NK
T cells. IL-4 production in response to anti-IgD occurs normally in
NK T cell-deficient mice (CD1-/- and B2
m-/-) (31, 34), and our analysis
of the frequency of Vß8+ CD4 T cells in the
IL-4R-/- mice makes it unlikely that the
IL-4 producers are NK T cells (Fig. 3).
Further evidence for the IL-4-independent appearance of IL-4-producing
Th2 cells is from a study in IL-4R-/- and in
Stat6-/- mice infected with Schistosoma
mansoni. CD4+ T cells from these mice
produce IL-4, although at a lower frequency than do
CD4+ T cells from infected WT mice
(35). Careful analysis of the CD4 cells from the mutant
mice and of schistosome egg Ag-specific T cell clones derived from them
showed that the cells had the capacity to produce IL-5 as well as IL-4,
strengthening the contention that they were authentic Th2 cells.
Another in vivo system in which IL-4-independent induction of Th2 responses occurs is in BCL6-/- mice. These mice develop a severe Th2-type myocarditis and pulmonary vasculitis, marked by eosinophil infiltration and by the production of IL-4, IL-5, IL-10, and IL-13 (36). BCL6 has been shown to be capable of opposing Stat6-induced transcription of some genes (36); nonetheless, a similar syndrome occurs in (BCL6xSTAT6)-/- mice, indicating that in the absence of BCL6, a STAT6-independent pathway of priming for IL-4 production is revealed (37).
Ouyang and colleagues have recently reported that a proportion of
DO11.10 TCR transgenic STAT6-/- cells develop
into IL-4-producers when primed in vitro (38). They
demonstrated that in such cells GATA3 mRNA levels were elevated, and
that the DNase I hypersensitivity had been induced in the second intron
of the IL-4 gene, consistent with the concept that the pathway of Th2
priming, although IL-4-independent, was still GATA3 dependent. This
result and the results from the
(BCL6xSTAT6)-/- mice are consistent with the
existence of a single common pathway for Th2 differentiation involving
GATA3. This pathway is most efficiently stimulated through
IL-4R/STAT6 activation, but it may also be induced through some
other mechanism(s), possibly through TCR and accessory molecule
engagement with appropriate APCs. Such IL-4-independent priming has
been reported when human DC2 dendritic cells, but not DC1 cells, have
been used to stimulate naive (CD45RO+) CD4 T
cells to become IL-4 producers (39). Furthermore, it has
been reported that APCs that fail to express ICAM-1 efficiently induce
Th2 responses (40, 41).
Thus, these results indicate that some conventional
CD4+ T cells can produce IL-4 in response to
Ag-mediated T cell activation, and that such IL-4 can then drive the
bulk of the responding CD4 T cells to differentiate into polarized Th2
cells. The factors that govern the initial production of IL-4 are a
complex interplay of peptide dose, costimulatory molecules, the
strength and repetition of the stimulus, and the presence of
down-regulatory cytokines, such as IFN- (19, 21, 42, 43, 44). The DO11.10/scid
IL-4R-/- mutants may be useful in dissecting
these parameters.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: NK T cells, NK1.1+, CD4+ T cells; WT, wild-type; LN, lymph node; cRPMI, complete RPMI; KO, knockout; L, ligand.
Received for publication February 23, 2000. Accepted for publication July 12, 2000.
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D. R. Patel, M. H. Kaplan, and C.-H. Chang Altered Th1 Cell Differentiation Programming by CIITA Deficiency J. Immunol., November 1, 2004; 173(9): 5501 - 5508. [Abstract] [Full Text] [PDF]
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A. Rivas-Carvalho, M. A. Meraz-Rios, L. Santos-Argumedo, S. Bajana, G. Soldevila, M. E. Moreno-Garcia, and C. Sanchez-Torres CD16+ human monocyte-derived dendritic cells matured with different and unrelated stimuli promote similar allogeneic Th2 responses: regulation by pro- and anti-inflammatory cytokines Int. Immunol., September 1, 2004; 16(9): 1251 - 1263. [Abstract] [Full Text] [PDF]
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D. Jankovic, M. C. Kullberg, P. Caspar, and A. Sher Parasite-Induced Th2 Polarization Is Associated with Down-Regulated Dendritic Cell Responsiveness to Th1 Stimuli and a Transient Delay in T Lymphocyte Cycling J. Immunol., August 15, 2004; 173(4): 2419 - 2427. [Abstract] [Full Text] [PDF]
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A. E. Kelly-Welch, M. E. F. Melo, E. Smith, A. Q. Ford, C. Haudenschild, N. Noben-Trauth, and A. D. Keegan Complex Role of the IL-4 Receptor {alpha} in a Murine Model of Airway Inflammation: Expression of the IL-4 Receptor {alpha} on Nonlymphoid Cells of Bone Marrow Origin Contributes to Severity of Inflammation J. Immunol., April 1, 2004; 172(7): 4545 - 4555. [Abstract] [Full Text] [PDF]
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B. J. Manfras, S. Reuter, T. Wendland, B. O. Boehm, and P. Kern Impeded Th1 CD4 memory T cell generation in chronic-persisting liver infection with Echinococcus multilocularis Int. Immunol., January 1, 2004; 16(1): 43 - 50. [Abstract] [Full Text] [PDF]
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F. Maszyna, H. Hoff, D. Kunkel, A. Radbruch, and M. C. Brunner-Weinzierl Diversity of Clonal T Cell Proliferation Is Mediated by Differential Expression of CD152 (CTLA-4) on the Cell Surface of Activated Individual T Lymphocytes J. Immunol., October 1, 2003; 171(7): 3459 - 3466. [Abstract] [Full Text] [PDF]
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N. Noben-Trauth, R. Lira, H. Nagase, W. E. Paul, and D. L. Sacks The Relative Contribution of IL-4 Receptor Signaling and IL-10 to Susceptibility to Leishmania major J. Immunol., May 15, 2003; 170(10): 5152 - 5158. [Abstract] [Full Text] [PDF]
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P.-J. Linton, B. Bautista, E. Biederman, E. S. Bradley, J. Harbertson, R. M. Kondrack, R. C. Padrick, and L. M. Bradley Costimulation via OX40L Expressed by B Cells Is Sufficient to Determine the Extent of Primary CD4 Cell Expansion and Th2 Cytokine Secretion In Vivo J. Exp. Med., April 7, 2003; 197(7): 875 - 883. [Abstract] [Full Text] [PDF]
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 A. Metwali, A. Blum, D. E. Elliott, and J. V. Weinstock Interleukin-4 Receptor {alpha} Chain and STAT6 Signaling Inhibit Gamma Interferon but Not Th2 Cytokine Expression within Schistosome Granulomas Infect. Immun., October 1, 2002; 70(10): 5651 - 5658. [Abstract] [Full Text] [PDF]
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K. Venuprasad, P. P. Banerjee, S. Chattopadhyay, S. Sharma, S. Pal, P. B. Parab, D. Mitra, and B. Saha Human Neutrophil-Expressed CD28 Interacts with Macrophage B7 to Induce Phosphatidylinositol 3-Kinase-Dependent IFN-{gamma} Secretion and Restriction of Leishmania Growth J. Immunol., July 15, 2002; 169(2): 920 - 928. [Abstract] [Full Text] [PDF]
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J. L. Brogdon, D. Leitenberg, and K. Bottomly The Potency of TCR Signaling Differentially Regulates NFATc/p Activity and Early IL-4 Transcription in Naive CD4+ T Cells J. Immunol., April 15, 2002; 168(8): 3825 - 3832. [Abstract] [Full Text] [PDF]
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A. Y. Karulin, M. D. Hesse, H. C. Yip, and P. V. Lehmann Indirect IL-4 Pathway in Type 1 Immunity J. Immunol., January 15, 2002; 168(2): 545 - 553. [Abstract] [Full Text] [PDF]
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S. C. Henderson, M. M. Kamdar, and A. Bamezai Ly-6A.2 Expression Regulates Antigen-Specific CD4+ T Cell Proliferation and Cytokine Production J. Immunol., January 1, 2002; 168(1): 118 - 126. [Abstract] [Full Text] [PDF]
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G. Foucras, A. Gallard, C. Coureau, J.-M. Kanellopoulos, and J.-C. Guery Chronic Soluble Antigen Sensitization Primes a Unique Memory/Effector T Cell Repertoire Associated with Th2 Phenotype Acquisition In Vivo J. Immunol., January 1, 2002; 168(1): 179 - 187. [Abstract] [Full Text] [PDF]
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S. B. Campbell, T. Komata, and A. Kelso CD4 Ligation Promotes the IL-4-Independent Development of IL-4-Producing Clones from Naive CD4+ T Cells J. Immunol., November 15, 2001; 167(10): 5610 - 5619. [Abstract] [Full Text] [PDF]
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R. Maldonado-Lopez, C. Maliszewski, J. Urbain, and M. Moser Cytokines Regulate the Capacity of CD8{alpha}+ and CD8{alpha}- Dendritic Cells to Prime Th1/Th2 Cells In Vivo J. Immunol., October 15, 2001; 167(8): 4345 - 4350. [Abstract] [Full Text] [PDF]
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