| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Division of Immunology, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, and Cincinnati Veterans Administration Medical Center, Cincinnati, OH 45220; and
Department of Immunology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA 94304
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The best-characterized T cell population that produces IL-4 without
IL-4 priming expresses CD3, CD4, TCR 
ß, and (in appropriate mouse
strains) NK1.1 (11). NK1.1+ T cells have a highly
restricted TCR repertoire and recognize the nonpolymorphic MHC class I
Ag CD1 (12). Even though NK 1.1+ T cells express CD4,
neither this molecule nor MHC class II has a critical role in their
selection or activation (13, 14). As a result, the NK1.1+ T
cell population is greatly reduced in mice deficient for either CD1
(15, 16, 17) or ß2-microglobulin (13, 18) (which is required
for CD1 expression) (19), but not in mice deficient for class II
MHC (18).
The importance of NK1.1+ T cells for the generation of an IL-4 response was suggested by the failure of spleen cells from ß2-microglobulin-deficient mice to make IL-4 responses when stimulated in vivo by i.v. injection of anti-CD3 mAbs, which directly activate T cells (18). ß2-Microglobulin-deficient mice also made greatly decreased IL-4-dependent IgE responses to a goat Ab to mouse IgD (18), which activates T cells more physiologically than anti-CD3 mAb, in that it requires presentation and T cell recognition of determinants derived from the anti-IgD Ab (20). These observations and a report that anti-IgD Abs induce an IgE response in class II MHC-deficient mice (18) suggested that anti-IgD Ab-induced B cell activation might up-regulate the expression or enhance the presentation of B cell CD1 to NK1.1+ T cells, resulting in activation of these cells and increased secretion of IL-4 that could stimulate an IgE response.
Some observations, however, have been difficult to reconcile with this attractive model. First, Ab responses and IL-4 responses to anti-IgD Abs can be suppressed by tolerizing mice to determinants on the anti-IgD Ab (21, 22). This should not be the case if the IgE response were driven entirely by an NK1.1+ T cell response to CD1. Second, mice deficient in CD1 make a normal IgE response to anti-IgD Ab (15, 16, 17) even though their spleen cells fail to make an IL-4 response to anti-CD3 mAb (18). Third, unlike the IgE response to anti-IgD Ab, IgE responses to OVA administered with alum adjuvant or to parasite infections appear to be normal in ß2-microglobulin-deficient mice (23, 24, 25). This finding suggested that conventional Ags induce IL-4 production differently than anti-IgD Ab and raised doubts about the importance of CD1 and the NK1.1+ T cell for the induction of T cell IL-4 production.
The studies described in this paper were performed to test an alternative explanation for the failure of ß2-microglobulin-deficient mice to produce IL-4 and IgE in response to anti-IgD Ab that is consistent with all of these observations. ß2-Microglobulin has recently been shown to be required to allow the expression of a nonpolymorphic MHC class I-related molecule, the neonatal gut transport receptor (FcRn), which has a critical role in preventing cellular degradation of IgG (26, 27). As a result, IgG has a greatly reduced half-life in ß2-microglobulin-deficient mice. This rapid loss of IgG Ab in ß2-microglobulin-deficient mice might be relevant to the failure of a single injection of anti-IgD Ab to induce an IgE response in these mice, because anti-IgD Ab must be present for 5 days to induce an Ab response in normal mice (28). To test this possibility, we examined the ability of repeated daily injections of anti-IgD Ab to stimulate IL-4 and IgE responses in wild-type and ß2-microglobulin-deficient mice.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
ß2-Microglobulin-deficient mice (29) back-crossed for 10 generations onto a BALB/cJ background were obtained from The Jackson Laboratory (Bar Harbor, ME) and bred at DNAX as described (25). BALB/c wild-type mice were obtained from the Small Animals Division of the National Cancer Institute, Frederick, MD. Class II MHC-deficient (I-Aß-) mice (30) on a C57BL/6 background, as well as C57BL/6 wild-type mice, were generous gifts of Dr. Laurie Glimscher, Harvard University School of Public Health, Boston, MA, and Dr. Albert Bendelac, Princeton University, Princeton, NJ. Additional C57BL/6 wild-type mice were purchased from the Small Animals Division of the National Cancer Institute. Mice heterozygous for a nonfunctional Stat6 gene (31) were the generous gift of Dr. James Ihle, St. Jude Children’s Research Hospital, Memphis, TN. These mice were bred at the Cincinnati Veterans Administration Medical Center animal facility to obtain wild-type and homozygous Stat6-deficient mice on the same mixed C57BL/6-129 background.
Antibodies
Affinity-purified goat anti-mouse IgD Ab
(GM
),4 rabbit
anti-mouse IgG2 Ab (which binds IgG2a and IgG2b), and goat
anti-rabbit IgG were prepared as described (21, 32). Two
anti-IgD mAb-producing hybridomas, Ha/1 (which
secretes mouse IgG2b of the b allotype that binds IgDFc of
the a allotype) (33) and FF1-4D5 (which secretes mouse IgG2a
of the b allotype that binds IgDFd of the a
allotype) (34) were grown as ascites in Pristane-primed (BALB/c x
C57BL/6)F1 mice and were purified from ascites (32).
GM stimulates IL-4 and IgE production in both BALB/c and C57BL/6
mice; a combination of the two anti-IgD mAbs stimulates substantial
IgE and IL-4 responses only in mice that express Ig of the a
allotype (Ref. 35 and F. Finkelman, unpublished data). Monoclonal mouse
IgD was purified from ascites produced by growing the plasmacytoma
TEPC-1017 in Pristane (Sigma, St. Louis, Mo)-primed BALB/c mice (32).
Monoclonal rat IgG2a mAbs, which bind to different epitopes of IL-4,
and a monoclonal hamster mAb that binds and cross-links CD3 were
purified from ascites produced by growing BVD4-1D11.2 (36) and
BVD6-24G2.3 (36), or 2C11 (37), respectively, in Pristane-primed
athymic nude mice. 2C11 was obtained from the American Type Culture
Collection, Rockville, MD.
Ab determinations
Total serum IgG1 was determined by radial immunodiffusion using
a polyclonal anti-IgG1 antiserum purchased from The Binding Site
(Manchester, U.K.). Total serum IgE was determined by ELISA, using the
rat IgG mAbs EM-95 and RIE4 (38, 39), which bind to distinct sites on
mouse IgE. IgG1 anti-goat IgG was titered by ELISA, using
affinity-purified polyclonal rabbit anti-mouse IgG1 Ab and alkaline
phosphatase-labeled goat anti-rabbit IgG. Relative serum
concentrations of IgG2a and IgG2b anti-IgD mAbs (FF1-4D5 and
Ha/1) were determined by ELISA, using wells coated
with TEPC-1017 and rabbit anti-mouse 
2 Ab and
alkaline phosphatase-labeled goat anti-rabbit IgG to detect
bound Ab.
IL-4 determinations
In vivo IL-4 production was determined by the Cincinnati
cytokine capture assay (CCCA), which will be described in detail in a
separate paper (manuscript in preparation). Mice were injected i.v.
with 10 µg of a neutralizing biotin-labeled anti-IL-4 mAb
(BVD4-1D11.2). This Ab "captures" secreted IL-4 and prevents its
degradation and excretion, so that secreted IL-4 accumulates in
extracellular fluid, including plasma. Mice were bled 2 to 24 h
after injection of biotinanti-IL-4 mAb, and serum was prepared.
Concentrations of biotin-anti-IL-4/IL-4 complexes in serum were
determined by ELISA, using Immulon II plates (Dynatech, Chantilly, VA)
coated with BVD6.24G2.3, an Ab to an IL-4 determinant distinct from
that bound by BVD4.1D11.2. Following addition of serial 1:4 dilutions
of sera or a standard that contains 2 ng of IL-4 and 200 ng of
biotin-BVD4.1D11.2, microtiter plate wells were filled sequentially
with alkaline phosphatase-streptavidin (Jackson ImmunoResearch, West
Grove, PA), biotin-labeled AECM-Ficoll, a second incubation with
alkaline phosphatase-streptavidin, and substrate
(p-nitrophenylphosphate, Behring Diagnostics, La
Jolla, CA), then incubated overnight at room temperature and read with
a Labsystems Multiskan MS ELISA reader (Helsinki, Finland) at
A405. This assay had a sensitivity of 
2 pg/ml.
Preliminary experiments established the specificity of the assay for
IL-4 as follows: 1) IL-4 was undetectable (<2 pg/ml) in sera from
anti-CD3 mAb-treated C57BL/6.IL-4-deficient mice but was detectable
at a concentration of 7.4 pg/ml in sera from untreated C57BL/6
wild-type mice and at a concentration of 18,120 pg/ml in sera from
anti-CD3 mAb-treated C57BL/6 wild-type mice; and 2) if microtiter
plate wells were not coated with the anti-IL-4 capture mAb,
BVD6.24G2.3, no IL-4 (<2pg/ml) was detectable in a standard solution
that contained 2 ng/ml of rIL-4 and 200 ng of biotin-BVD4.1D11.2 or in
a serum that contained >10 ng/ml of IL-4 (data not shown).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To determine whether ß2-microglobulin-deficient
mice could be induced to produce IL-4 and IgE in response to
anti-IgD mAbs, wild-type or
ß2-microglobulin-deficient mice on a BALB/c background
(5/group) were bled, then injected i.v. with 100 µg each of FF1-4D5
and Ha/1 anti-IgD mAbs on day 0 only or once daily
on days 0 through 4. Serum obtained 4 days after the first injection of
anti-IgD mAbs was titered by ELISA for IgG2a plus IgG2b
anti-IgD Ab. Anti-IgD levels were at least 40-fold higher in
wild-type mice than in ß2-microglobulin-deficient mice
that had been injected only once with the anti-IgD mAbs (Fig. 1
), in keeping with the reported short
IgG life span in ß2-microglobulin-deficient mice (IgG
(26, 27). As expected, anti-IgD mAb levels were considerably higher
in both wild-type and ß2-microglobulin-deficient mice
that had received daily anti-IgD mAb injections.
|
). Serum IgE
reached peak levels 8 days after anti-IgD mAb injection in all
mice, at which time they were increased 15-fold above baseline
levels in wild-type mice that had been treated once or five times with
anti-IgD mAb and 10-fold above baseline levels in
ß2-microglobulin-deficient mice that had been treated
five times with anti-IgD mAb. In contrast, serum IgE did not
increase in ß2-microglobulin-deficient mice that had been
treated only once with anti-IgD mAb (Fig. 1). Serum IgG1 levels
also increased substantially in wild-type mice that had been injected
once or five times with anti-IgD and in
ß2-microglobulin-deficient mice that had been injected
five times with anti-IgD, but not in
ß2-microglobulin-deficient mice that had only been
injected once with anti-IgD Ab (Fig. 1). Thus,
ß2-microglobulin-deficient mice are able to make
relatively normal IL-4, IgE, and IgG1 responses to anti-IgD Ab,
provided that serum anti-IgD levels are maintained. MHC class II-deficient mice fail to make IL-4, IgG1, or IgE responses to anti-IgD Ab
Our observation that ß2-microglobulin-deficient
mice can make IL-4 and IgE responses to anti-IgD Ab did not
eliminate the possibility that the CD1-responsive T cells that are
absent in these mice can also contribute to anti-IgD Ab-induced
IL-4 and IgE responses. If CD1-responsive T cells stimulate B cells to
generate an IgE response to anti-IgD Ab, this Ab should stimulate
class II MHC-deficient mice, which have CD1-responsive CD4+
T cells, to make IL-4 and IgE responses. Such an observation has been
reported (18). In an attempt to confirm this observation, wild-type and
MHC class II-deficient mice, on a C57BL/6 background, were injected
with biotin-anti-IL-4 mAb 1 day before and 3, 5, and 7 days after
injection of 800 µg of GM. Mice were bled 1 day after each
biotin-anti-IL-4 mAb injection, and serum IL-4 levels were
determined. Similar baseline levels of IL-4, which were higher than
those observed in BALB/c mice, were detected in C57BL/6 wild-type and
class II MHC-deficient mice (Fig. 2).
IL-4 levels were increased approximately sixfold in wild-type mice 6
days after GM injection, but remained unchanged from baseline
levels in GM-treated class II MHC-deficient mice. In a separate
experiment, wild-type and MHC class II-deficient mice were pre-bled,
then bled again 8 and 10 days after injection of 800 µg of GM.
Total IgE, total IgG1, and IgG1 anti-goat IgG levels increased
70-fold, 18-fold, and >400-fold, respectively, 10 days after
GM injection in wild-type mice, but did not increase in MHC class
II-deficient mice (Fig. 2). Similar results were seen in a third
experiment in which mice were injected with 400 µg of GM plus
400 µg of normal goat IgG, with the exception that 100-fold and
3-fold increases in serum IgE levels were detected in wild-type and
class II MHC-deficient mice, respectively (data not shown).
|
To make certain that the class II MHC-deficient mice used in our
experiments were capable of making IL-4 responses when appropriately
stimulated, class II MHC-deficient and wild-type mice were injected
i.v. with biotin-labeled BVD4.1D11.2 and either saline or 10 µg of
anti-CD3 mAb (a higher dose than has been used in some other
studies (18)). Mice were bled 1 day later. Serum IL-4 levels,
determined by ELISA, were increased >100-fold in both wild-type and
class II MHC-deficient mice at this time (Fig. 3, upper panel).
Because lymph node cells from
ß2-microglobulin-deficient mice have been found by
one of us (R.L.C.) to rapidly express the IL-4 gene in response to
footpad injection of anti-CD3 mAb (25), we also compared the
abilities of wild-type and ß2-microglobulin-deficient
mice to make IL-4 responses to this mAb. Mice were bled in this
experiment only 2 h after i.v. injection of biotin-anti-IL-4
and saline or anti-CD3 mAb injection to minimize the effect of the
more rapid catabolism of IgG Abs in the
ß2-microglobulin-deficient mice. Anti-CD3 mAb treatment
increased serum IL-4 levels by a factor of 1000 in the wild-type
mice, and by a factor of 300 in the
ß2-microglobulin-deficient mice (Fig. 3, lower
panel).
|
M
The observation that anti-CD3 mAb induces a large, rapid IL-4
response in ß2-microglobulin-deficient mice was
consistent with the view that a population of CD1-nonrestricted T cells
primes naive, conventional CD4+ T cells to make IL-4 in
these mice. Another possible interpretation, however, was that IL-4 is
not required to prime CD4+ T cells to produce IL-4 in
anti-IgD Ab-treated mice. Because IL-4 priming of T cells to
produce IL-4 requires signal transduction through Stat6 (31, 40), and
because CD4+ T cells are the source of nearly all IL-4 made
in GM-treated mice (41, 42), we were able to test the latter
possibility by comparing IL-4 responses made by wild-type and
Stat6-deficient mice to GM. Both wild-type and Stat6-deficient
mice produced small amounts of IL-4 for the first 4 days after GM
injection but large amounts of IL-4 starting on day 5. IL-4 production
by the Stat6-deficient mice, at all time points studied, was at least
as large as that made by the wild-type mice (Fig. 4). Thus, IL-4 does not appear to be
required to prime CD4+ T cells to make IL-4 in response to
GM Ab. As compared with C57BL/6 mice (Fig. 2), wild-type and
Stat6-deficient mice on a mixed C57BL/6–129 background had lower
baseline IL-4 production and higher and more sustained IL-4 responses
to GM. As previously reported (31, 40, 43), anti-IgD
Ab-treated Stat6-deficient mice failed to produce IgE (Fig. 4
legend).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
3 days) than the in vivo IL-4 mRNA
response to anti-CD3 Ab (30 min) (41, 42, 44).
The data presented here provide an explanation for these apparently
contradictory results. Because anti-IgD Ab must be present for 5
days to stimulate Ab production (28) and IgG Ab has a short half-life
in ß2-microglobulin-deficient mice (26, 27), a single
injection of IgG anti-IgD Ab does not maintain anti-IgD Ab
levels long enough to stimulate IL-4 and Ab production. Maintaining
anti-IgD Ab concentrations through daily injection of anti-IgD
Ab allows these mice to make relatively normal IL-4 and IgE responses
(Fig. 1). The normal in vivo half-life of proteins other than IgG in
ß2-microglobulin-deficient mice (26, 27) probably
accounts for their relatively normal IgE responses to Ags other than
anti-IgD Ab. Thus, the inability of
ß2-microglobulin-deficient mice to make IL-4 responses to
a single injection of anti-IgD Ab reflects a requirement for
relatively prolonged Ag stimulation, rather than a requirement for
NK1+ T cells, for the induction of an IL-4 response. Even
though NK1+ T cells are capable of making large and rapid
IL-4 responses to appropriate stimuli (10), the NK1+ T cell
deficiency in ß2-microglobulin-deficient mice is probably
irrelevant to their inability to make IL-4 responses to a single dose
of anti-IgD Ab.
The failure of MHC class II-deficient mice, in our study, to make IL-4 or Ab responses to anti-IgD Ab is consistent with the view that the IL-4 response to anti-IgD Ab is made by conventional CD4+ T cells, which are restricted by MHC class II, rather than by NK1+ T cells, which are restricted by CD1 (11). We cannot account for why a previous study, that used the same mouse strain used in our experiments and anti-IgD Ab produced in our laboratory, observed that the IgE response to anti-IgD Ab is MHC class II independent (18); however, one of the investigators in that study has since confirmed our result (A. Bendelac, unpublished observation).
Anti-IgD Ab-induced IL-4 responses, thus, differ from anti-CD3 mAb-induced IL-4 responses both in their dependence on MHC class II Ag presentation and in their lack of dependence on NK1+ T cells. These observations suggest that IL-4 responses to anti-CD3 Ab differ fundamentally from responses to anti-IgD or conventional Ags. The former response is induced directly by cross-linking TCR on a relatively small splenic T cell population that responds to a nonpolymorphic MHC class I-related Ag and on a still undefined lymph node population (25), while the latter response is induced by MHC class II-dependent cross-linking of the TCR on an Ag-specific population of conventional CD4+ T cells. We suggest that the rapid IL-4 responses made by CD1-responsive and related T cells that are not MHC class II restricted may be relevant for priming, augmenting, or sustaining responses to microbial Ags that can be presented by CD1 and related nonconventional MHC class I molecules, but may have little role in the generation of cytokine or Ab responses to soluble protein Ags.
Our findings leave open the possibility that the lymph node T
cell population that rapidly produces IL-4 in response to anti-CD3
mAb in ß2-microglobulin-deficient mice (25) primes
conventional CD4+ T cells in these mice to make IL-4.
However, our observation that IL-4 responses occur with the same
magnitude and kinetics in Stat6-deficient mice as in wild-type mice
makes it more likely that IL-4 priming is not required to induce T
cells to secrete IL-4 in response to anti-IgD Ab. CD4+
T cells from Stat6-deficient mice, unlike CD4+ T cells from
normal mice, are not primed by IL-4 to produce IL-4: they do not
secrete IL-4 or other type 2 cytokines following in vitro stimulation
with IL-4 plus IL-2, anti-IFN- mAb, and anti-CD3 mAb, with
or without anti-CD28 mAb (31, 40). The lack of a requirement for in
vivo priming for IL-4 secretion in anti-IgD Ab-treated mice is
consistent with our previous inability to suppress IL-4 mRNA responses
to anti-IgD Ab with a combination of anti-IL-4 and
anti-IL-4 receptor mAbs (F. Finkelman and W. C. Gause,
unpublished observations) and with recent observations that IL-4 mRNA
responses to GM are normal or above normal in BALB/c.IL-4
receptor -chain-deficient mice (N. Noben-Trauth, unpublished
observation). In contrast, IL-4 responses in mice infected with
gastrointestinal nematode parasites, as determined by IL-4 mRNA levels
or by in vitro restimulation with anti-CD3 mAb, are present but
considerably reduced in Stat6-deficient and IL-4R-deficient mice
(43, 45) and in wild-type mice that have been treated with
anti-IL-4 and anti-IL-4R mAbs (J. Urban, F. Finkelman, and
W. C. Gause, unpublished observations). Recent studies of IL-4
production in Heligmosomoides polygyrus-infected wild-type
and Stat6-deficient mice suggest that IL-4 is not required to induce
naive CD4+ T cells to produce the initial IL-4 response,
but rather amplifies later IL-4 production (F. Finkelman and J. Urban,
unpublished observation).
Although our observations demonstrate that NK1+ T cells and
IL-4 priming of T cells are not involved in anti-IgD Ab stimulation
of a large IL-4 response that is made by CD4+ T cells (42),
they do not identify a substitute mechanism that explains why
anti-IgD Ab is such a strong stimulus for IL-4 production. We
propose that anti-IgD Ab is a powerful stimulus of IL-4 production
for three reasons. 1) Anti-IgD Ab strongly stimulates T cell activation
(28, 46). This is probably because this Ab directly activates the great
majority of mature B cells by cross-linking their membrane (m) IgD
(46). Anti-IgD Ab is then internalized, processed, and presented by
these B cells (47). The large number of these Ag-presenting B cells as
well as their increased expression of MHC class II (48) and B7-2 (F.
Finkelman, unpublished observations) probably both contribute to their
T cell-activating ability. IL-4 production in this system is B7
dependent (49) and MHC class II dependent and requires T cell
recognition of the anti-IgD Ab as foreign (20, 21). 2) Because
anti-IgD Ab is focused directly onto B cells, B cells probably are
responsible for most of the Ag presentation in anti-IgD Ab-injected
mice (47). B cell Ag presentation has been shown by some investigators
to predispose to an IL-4, rather than an IFN- response (50). We
suspect that this finding reflects the relative inability of B cells to
produce cytokines, such as IL-12, IFN-, and IFN-ß, that suppress
IL-4 production and stimulate IFN- production (51, 52, 53, 54), although we
cannot rule out the possibility that activated B cells express or
secrete molecules that specifically stimulate IL-4 production or
suppress IFN- production. We doubt that there is anything specific
about B cell stimulation through mIgD that accounts for the large IL-4
response to anti-IgD Ab; recent studies demonstrate that
anti-IgM Ab stimulates a large IL-4 response when injected into
mice that express murine IgM but no secreted IgM (M. Mori, J.
Chen, and F. Finkelman, unpublished observations). 3) Anti-IgD Ab is
presented to T cells for several days. In normal mice, the long
half-life of IgG anti-IgD Ab allows T cells to be stimulated
by Ag-presenting B cells for several days after a single injection of
anti-IgD Ab. Ag persistence, and consequently, Ag presentation to T
cells over a long period of time is also characteristic of other strong
stimuli of IL-4 responses, such as alum-precipitated Ag and nematode
parasites.
In summary, we propose that in vivo IL-4 production during a primary response by naive T cells can be induced by at least two different mechanisms: 1) the production of IL-4 early in the response primes IL-4 production by differentiating T cells; and 2) prolonged TCR stimulation with CD28 costimulation stimulates naive CD4+ T cells to differentiate into IL-4-secreting cells in the absence of IL-4 priming, provided that cytokines that inhibit IL-4 production are also absent or present in low concentration. Because the latter mechanism may be difficult to mimic in vitro, we believe that in vivo studies will be required to determine the relative importance of these two mechanisms in the generation of IL-4 responses to different immunogens.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 The studies reported in this article were conducted according to the principles set forth in the Guide for Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources, National Research Council, HHS Publication No. (NIH) 85-23, revised 1985.
3 Address correspondence and reprint requests to Dr. Fred Finkelman, Division of Immunology, Department of Medicine, University of Cincinnati College of Medicine, P.O. Box 670563, Cincinnati, OH 45267. E-mail address:
4 Abbreviations used in this paper: GM, goat anti-mouse IgD Ab; CCCA, Cincinnati cytokine capture assay; m, membrane.
Received for publication October 7, 1997. Accepted for publication December 9, 1997.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
receptors and produce IL-4 are highly enriched in basophils. Proc. Natl. Acad. Sci. USA 88:2835. antibodies. I: Determinants of B lymphocyte activating properties. J. Immunol. l 35:2382.
of immunoglobulin isotype selection and lymphokine production in mice. J. Exp. Med. 174:1179.This article has been cited by other articles:
|
|
 |
|
  T. Chitnis, A. D. Salama, M. J. Grusby, M. H. Sayegh, and S. J. Khoury Defining Th1 and Th2 Immune Responses in a Reciprocal Cytokine Environment In Vivo J. Immunol., April 1, 2004; 172(7): 4260 - 4265. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. E. S. Nieuwenhuis, M. F. Neurath, N. Corazza, H. Iijima, J. Trgovcich, S. Wirtz, J. Glickman, D. Bailey, M. Yoshida, P. R. Galle, et al. Disruption of T helper 2-immune responses in Epstein-Barr virus-induced gene 3-deficient mice PNAS, December 24, 2002; 99(26): 16951 - 16956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Noben-Trauth, J. Hu-Li, and W. E. Paul Conventional, Naive CD4+ T Cells Provide an Initial Source of IL-4 During Th2 Differentiation J. Immunol., October 1, 2000; 165(7): 3620 - 3625. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Jankovic, M. C. Kullberg, N. Noben-Trauth, P. Caspar, W. E. Paul, and A. Sher Single Cell Analysis Reveals That IL-4 Receptor/Stat6 Signaling Is Not Required for the In Vivo or In Vitro Development of CD4+ Lymphocytes with a Th2 Cytokine Profile J. Immunol., March 15, 2000; 164(6): 3047 - 3055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. D. Finkelman, S. C. Morris, T. Orekhova, M. Mori, D. Donaldson, S. L. Reiner, N. L. Reilly, L. Schopf, and J. F. Urban Jr. Stat6 Regulation of In Vivo IL-4 Responses J. Immunol., March 1, 2000; 164(5): 2303 - 2310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. Wang, X. Y. Yang, R. A. Kirken, J. H. Resau, and W. L. Farrar Targeted disruption of Stat6 DNA binding activity by an oligonucleotide decoy blocks IL-4-driven TH2 cell response Blood, February 15, 2000; 95(4): 1249 - 1257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Brewer, M. Conacher, C. A. Hunter, M. Mohrs, F. Brombacher, and J. Alexander Aluminium Hydroxide Adjuvant Initiates Strong Antigen-Specific Th2 Responses in the Absence of IL-4- or IL-13-Mediated Signaling J. Immunol., December 15, 1999; 163(12): 6448 - 6454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Kaplan, A. L. Wurster, S. T. Smiley, and M. J. Grusby3 Stat6-Dependent and -Independent Pathways for IL-4 Production J. Immunol., December 15, 1999; 163(12): 6536 - 6540. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hill, E. Herlaar, A. Le Cardinal, G. van Heeke, and P. Nicklin Homologous Human and Murine Antisense Oligonucleotides Targeting Stat6 . Functional Effects on Germline Cepsilon Transcript Am. J. Respir. Cell Mol. Biol., December 1, 1999; 21(6): 728 - 737. [Abstract] [Full Text]
|
|
|
|
 |
|
 F. D. Finkelman and S. C. Morris Development of an assay to measure in vivo cytokine production in the mouse Int. Immunol., November 1, 1999; 11(11): 1811 - 1818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Payet, E. C. Woodward, and D. H. Conrad Humoral Response Suppression Observed with CD23 Transgenics J. Immunol., July 1, 1999; 163(1): 217 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. N. Georas, J. E. Cumberland, T. F. Burke, R. Chen, U. Schindler, and V. Casolaro Stat6 Inhibits Human Interleukin-4 Promoter Activity in T Cells Blood, December 15, 1998; 92(12): 4529 - 4538. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
