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CUTTING EDGE |
Committee on Immunology and Department of Pathology, Ben May Institute for Cancer Research, University of Chicago, Chicago, IL, 60637
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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, and lymphotoxin, have a major
proinflammatory role in cellular immunity to intracellular pathogens,
whereas Th2 cells, which secrete IL-4, IL-5, and IL-10, have a
predominant role in humoral immunity against extracellular parasites
(1, 2). Many factors regulate Th1/Th2 differentiation. Cytokines such
as IFN-, IL-12, and IL-4 have been shown to play a key role in
skewing the Th cell repertoire (2). In addition, the strength of
TCR-mediated signals (3, 4) and costimulatory molecules such as CD30
(5), 4–1BB (6), or CD28 (7) have been reported to regulate Th cell
differentiation. The nature of the APCs can also alter this
differentiation. Several groups have shown that B cells promote Th2
differentiation (8), while dendritic cells
(DCs),3 the major APCs in
initiation of primary immune responses (9), promote Th1 differentiation
(10, 11, 12). This property of DC is due, at least in part, to the
production of IL-12 by the DC, but could also reflect differences in
the level of MHC expression or in the nature of signals delivered
through certain costimulatory/adhesion molecules. In this study, we examined the role of CD28/B7 and LFA-1/ICAM interactions in the regulation of T cell proliferation and differentiation of naive T cells from DO11.10 transgenic mice that express a TCR specific to OVA 323–339 (13). The data suggest that the CD28/B7 and LFA-1/ICAM pathways have opposing roles in the regulation of naive T cell differentiation stimulated by "fresh" CD8- DCs, the most potent immunostimulatory cells of the spleen (9). Thus, DCs may promote Th1 development by suppressing Th2 development through the interaction of ICAM-1 and ICAM-2 with LFA-1.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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BALB/c mice were purchased from Frederick Cancer Research Facility (Frederick, MD) and maintained in a specific pathogen-free barrier facility at the University of Chicago (Chicago, IL). DO11.10 transgenic mice expressing a TCR specific for OVA peptide 323–339 presented in the context of I-Ad (13) were bred to BALB/c mice and then to RAG-2-deficient-mice (gift from Fred Alt, Harvard Medical School, Boston, MA) to generate DO11.10 x RAG-2-/- mice. TCR transgene expression and B cell deficiency were analyzed by FACS.
Culture medium, Abs, blocking reagents
mAbs 145-2C11 (anti-CD3 (14)), J11d (anti-murine CD24, ATCC TIB-183; American Type Culture Collection (ATCC), Manassas, VA), and MKD6 (anti-murine I-Ad (15)) were prepared in our laboratory. Purified mAbs Yn1/1.7.4 (anti-ICAM-1, ATCC CRL-1878) and M17/4.2 (anti-LFA-1, ATCC TIB-127) were a gift from Dr. Robert Hendricks (University of Pittsburgh, PA), and ascites of Yn1/1.7.4 were a gift from Dr. Jim Miller (University of Chicago). MIC2/4 (anti-ICAM-2) mAb was purchased from PharMingen (San Diego, CA). The murine (m)CTLA4Ig was obtained from Genetics Institute (Cambridge, MA).
Purification of T cells and APCs
T cells from spleen and lymph nodes of DO11.10 x
RAG-2-/- were purified after passage over nylon wool
columns, depletion of cells expressing CD24 (J11d) and MHC class II
(MKD6) with rabbit complement at 37°C for 45 min, and Ficol-Hypaque
gradient separation. For DC purification, low density BALB/c spleen
cells were prepared as previously described (16, 17). The recovered low
density cells, preincubated with 2.4G2 mAb to reduce nonspecific
binding, were stained with biotin-labeled N418 (anti-CD11c, ATCC
HB224) revealed by streptavidin-phycoerythrin, FITC-labeled 14-4-4S mAb
(anti-I-E, ATCC HB-32) and phycoerythrin-labeled 53–6.7
(anti-CD8
from PharMingen) mAbs in staining buffer (PBS/2%
FCS/5 mM EDTA). The CD8- DC population (I-E+,
CD11c+, CD8-) was sorted on a
FACStarPlus (Becton Dickinson, Mountain View, CA). Cells
were kept at 4°C in staining buffer throughout the procedure.
DC-depleted splenocytes were prepared by double staining with
biotin-labeled N418 revealed by streptavidin-phycoerythrin and
FITC-labeled 14-4-4S mAb, and then CD11c- cells were
sorted on a FACStarPlus.
Proliferation assays
Six thousand T cells were cultured with 2,000 irradiated CD8- DCs or 20,000 irradiated splenocytes depleted of DCs (1000 rad) in round-bottom 96-well culture plates in DMEM (Life Technologies, Grand Island, NY). The medium was supplemented with 10% FCS (Summit Biotechnology), 100 U/ml penicillin, 100 µg/ml streptomycin, 0.29 mM L-glutamine, nonessential amino acids, 10 mM HEPES, 5 x 10-5 M 2-ME, and 1 µg/ml OVA 323–339 peptide (University of Chicago Peptide Synthesis Facility). Proliferative responses were assessed at 96 h by adding 1 µCi/well of [3H]thymidine during the final 7–9 h of culture before harvesting and scintillation counting.
T cell stimulation for cytokine production
T cells (104/well) were stimulated in the same
culture medium used for the proliferation assay with 1 µg/ml
OVA peptide and purified CD8- DCs (2 x
103/well) in round-bottom 96-well culture plates. In some
assays, supernatants (20 µl/well) were collected at 40 h and
analyzed for IL-2 by ELISA. Alternatively, after 5 or 7 days, cells for
each culture condition were pooled, and live cells were recovered by
Ficol-Hypaque gradient centrifugation, washed twice in PBS, and
replated (2 x 105 cells/well in 400 µl) onto
anti-CD3-coated (145-2C11 at 1 µg/ml) 48-well plates.
Supernatants were harvested after 44 h and analyzed for cytokines
by ELISA (IL-2, IL-4, and IL-5 using commercial kits from Endogen,
Cambridge, MA, and IFN- using reagents kindly provided by Dr. Robert
Schreiber, Washington University (St. Louis, MO).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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In the spleen, the CD8- DC subpopulation is
considered the critical initiator of primary immune responses compared
with the other DC subset and other APCs (9, 17). In this study,
Ag-specific T cells from DO11.10 x RAG-2-/-
transgenic mice were used in in vitro assays to compare DCs and other
APCs in naive T cell proliferation and differentiation. DC
subpopulations and other APCs of the spleen were purified by
multiparameter flow cytometric cell sorting to avoid the necessity for
in vitro culture, which could modify their physiologic properties.
Naive CD4+ T cells were very poorly stimulated by
DC-depleted splenocytes. In contrast, proliferation of the TCR
transgenic cells stimulated by 10-fold less CD8- DCs was
increased by 50-fold. (Fig. 1
A). These results indicate
that DCs are the major, if not the only, APCs able to stimulate naive
DO11.10 T cells in vitro. Thus, additional experiments utilized the
CD8- DC population to study the role of costimulation in
proliferation and differentiation of naive T cells.
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The role of B7 in the proliferation of naive CD4+ T
cells was assessed by stimulating naive DO11.10 T cells with syngeneic
DCs in the presence of 1 µg/ml OVA peptide and 5 µg/ml mCTLA4Ig (a
soluble CD28 antagonist that binds with high affinity to the B7-1 and
B7-2 molecules). IL-2 production at day 2 was inhibited by 80% by
mCTLA4Ig, confirming the role of B7 costimulation in IL-2 production
(18). In contrast, T cell proliferation was inhibited by only 
50%
at day 4 with mCTLA4Ig (Fig. 1
B). This result differs from
previous reports in which late proliferation of T cells stimulated by
total splenocytes was almost completely inhibited in the presence of
CD28 blockade (19, 20). However, in those systems, macrophages and B
cells may play a role in the stimulation of T cells, especially as
mixed naive and memory T cell populations may be present in these
RAG+ mice. In fact, contrary to naive T cells, activated T
cells can be efficiently stimulated by B cells (21). Thus, stimulation
of pure naive T cells by DCs, as opposed to mixed T cell populations
stimulated by the different splenic APCs, may be less dependent on CD28
signaling for proliferative responses. One explanation for the
inability of mCTLA4Ig to fully block T cell proliferation is that DCs
express other costimulatory molecules that stimulate the T cells.
Blocking mAbs specific to ICAM-1 and ICAM-2 were used for the
examination of the role of LFA-1/ICAM interactions in Ag-specific T
cell proliferation in this model. The addition of blocking
anti-ICAM-1 mAb had only a minimal effect on both proliferation and
IL-2 growth factor production of DO11.10 T cells stimulated by DCs as
compared with control cultures. Furthermore, blocking ICAM-2/LFA-1
interaction did not inhibit T cell activation. There were no additive
effects of blocking both ICAM-1 and ICAM-2 (Fig. 1B).
Conflicting results have been reported on the role of ICAM/LFA-1 in T
cell proliferation. In artificial systems of T cell stimulation by
insect cells or fibroblasts transfected with MHC and costimulatory
molecules or by immobilized ICAM-1 and mAb to CD3, ICAM-1/LFA-1 seems
to be a major costimulatory pathway (22, 23, 24). Other studies using
blocking mAbs or ICAM-1- and LFA-1-deficient mice have concluded that
ICAM-1/LFA-1 interactions are dispensable in many settings (25, 26, 27, 28).
Our results suggest that proliferation of naive DO11.10
CD4+ T cell stimulated by DCs is only partially dependent
on LFA-1/ICAM-1 and LFA-1/ICAM-2 interactions (<20% inhibition in the
presence of blocking mAbs). Anti-LFA-1 mAb blocked 40% of the T cell
proliferative response and 80% of IL-2 production (data not shown).
The results can be explained in several ways. First, a third ligand of
LFA-1 that has been identified on human APCs may also exist in mice
(29). Alternatively, a regulatory LFA-1 signaling pathway exists that
is triggered by the anti-LFA-1 mAbs, as previously suggested (30).
Finally, the anti-LFA-1 mAb blocks the LFA-1/ICAM interactions more
efficiently than the combination of anti-ICAM-1 and anti-ICAM-2
mAbs.
Blocking CD28/B7 and LFA-1/ICAM costimulation inhibits and promotes Th2 cytokine production, respectively
As stated above, costimulatory events have been shown to
effect the differentiation of Th cells both in vitro and in vivo. Thus,
the role of CD28/B7 and LFA-1/ICAM-1 costimulation in Th
differentiation was examined. Naive CD4+ T cells from
DO11.10 x RAG2-/- were cultured with DCs and 1
µg/ml (0.5 µM) OVA 323–339 for 5 days. Since levels of IFN-,
IL-4, and IL-5 cytokines were not detected in the primary culture (data
not shown), cells were harvested and restimulated with immobilized
anti-CD3 for 2 days, and cytokines in the culture supernatant were
quantified by ELISA. In the absence of blocking reagents, the T cells
differentiated into a Th1-like phenotype, producing high levels of
IFN- (15–30 ng/ml) and low levels of IL-4 and IL-5 (0.15–0.5
ng/ml) (Fig. 2). Blocking B7
costimulation during primary culture with mCTLA4Ig completely
inhibited Th2 cytokine production, with less effect on IFN-
production (Fig. 2), as previously observed (7, 31).
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and IL-2 (Fig. 1B) production but significantly
enhanced Th2 responses. The production of IL-4 and IL-5 was increased
by 25- to 40-fold in the presence of anti-ICAM-1 mAb in primary
culture as compared with control cultures (Figs. 2 and 3). Furthermore, the addition of purified
anti-ICAM-2 mAb resulted, on average, in a 15-fold increase in IL-4
and IL-5 production as compared with the control culture (Fig. 3).
Thus, ICAM-2 regulated Th2 T cell differentiation, although apparently
less efficiently than ICAM-1. Blocking both ICAM-1 and ICAM-2 in
primary culture had a dramatic synergistic effect. Compared with
control culture, 100-1000 times more IL-4 and IL-5 was produced in the
presence of the combined mAb blockade. A similar increase of Th2
cytokines was observed in the presence of blocking anti-LFA-1 mAb
(Fig. 3). Since the CD28/B7 blockade and ICAM/LFA-1 blockade resulted
in opposite effects on Th cell development, combined treatments were
examined. Addition of mCTLA4Ig to the culture with blocking
anti-ICAM-1 mAb resulted in a significantly lower increase in Th2
cytokine production, suggesting that regulation of Th2 development by
LFA-1/ICAM was dominant but CD28/B7 dependent (data not shown). The
similar effect of anti-ICAMs and anti-LFA-1 mAbs strongly
suggests that the mAbs are indeed acting by blocking LFA-1/ICAM
interactions. However, ICAMs and LFA-1 molecules are expressed on T
cells. Therefore, we tested whether the anti-ICAM-1 and
anti-LFA-1 Abs have direct effects on T cells in the absence of
APCs. Purified T cells were stimulated with immobilized anti-CD3
plus anti-CD28. The addition of soluble anti-ICAM-1 or
anti-LFA-1 mAbs had no effect on Th2 cytokines in this assay,
supporting the hypothesis that the mAbs were acting by blocking
LFA-1/ICAM interactions between T cells and APCs (Table I).
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and 3) drive Th1
differentiation, whereas very low levels of peptides (0.01–0.04 µM)
induce Th2 differentiation (3). We do not believe that the increase of
Th2 cytokines observed after blocking LFA-1/ICAM interaction is due to
less signal 1 for several reasons. First, under conditions using lower
doses of OVA peptide, there was a significant inhibition of DO11.10 T
cell proliferation and a severe drop in IL-2 production (Ref. 3 and
data not shown). Such inhibition of T cell stimulation was not observed
with anti-ICAM-1 and anti-ICAM-2 blocking Abs (Fig. 1B). Second, the increase in Th2 cytokines is much
more dramatic with blocking anti-ICAM Abs (100- to 1000-fold
increase) than with lowering OVA peptide doses (4- to 10-fold increase;
Ref. 3 and data not shown). Third, whatever the dose of OVA peptide
(0.025, 0.1, 0.5, 1, or 50 µg/ml), blocking LFA-1/ICAM interactions
always resulted in an increase of Th2 cytokines (data not shown).
Finally, low doses of OVA peptide resulted in a decrease in IFN-
production (Ref. 3 and data not shown) which was not observed after
blocking both ICAM-1 and ICAM-2 molecules (Fig. 3). However, it is
possible that the increase in Th2 cytokines following the addition of
anti-LFA-1 Ab to the culture was due, in part, to a lower signal 1.
Indeed, with anti-LFA-1 Ab, but not with anti-ICAM-1 and
anti-ICAM-2 Abs, T cell proliferation was reduced in primary
culture, and IFN- and IL-2 inconstantly diminished in secondary
culture (Fig. 3). In summary, our findings show that the LFA-1/ICAM interactions have a major role in the regulation of IL-4 and IL-5 production by CD4+ T cells. The effect appears to be dominant because the ligation of CD28/B7 alone promotes Th2 cytokines, while coligation of LFA-1/ICAM is inhibitory. It should be emphasized that the effect of LFA-1/ICAM blockade is not limited to the DO11.10 system described herein. In separate studies, we have observed that the Th2 cytokines produced by C57BL/6 T cells responding to BALB/c APCs in an allogeneic MLR are enhanced by the addition of either anti-LFA-1 or anti-ICAM-1 mAbs (data not shown). Thus, the regulation of Th1/Th2 balance by LFA-1/ICAMs is effected in at least three different systems: Ag-specific stimulation; MLR and anti-CD3 Ab stimulation. In addition, Th2 cytokine production was observed using T cells from the Th2-prone BALB/c mice, the Th1-prone C57BL/6 mice, and human T cells (33).
The mechanism by which LFA-1/ICAM interactions suppress Th2 development
is unclear. However, it is unlikely that decreased adhesion or the
strength of signal 1 is responsible. We believe it is more likely that
unique signals are delivered via this pathway, either into the T cells
or perhaps the DCs that inhibits Th2 development. In a simple system in
human, coimmobilized anti-CD3 and ICAM-1 resulted in the
differentiation of naive T cells into IFN--secreting cells
consistent with the existence of LFA-1 signaling into T cells (33). Our
results are particularly relevant to ongoing clinical studies in which
the benefits of blocking LFA-1/ICAM interactions in allograft rejection
and autoimmunity are being examined. Our findings suggest that part of
the beneficial effects of these therapies may be mediated by an
increase of Th2 cytokines, which have anti-inflammatory properties
(1).
Note added in proof. Similar observations that Th2 cytokine production is regulated by ICAM/LFA-1 interaction has been reported by C. R. Luksch, O. Winqvist, N. E. Ozaki, L. Karlsson, M. R. Jackson, P. H. Peterson, and S. R. Webb.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jeffrey A. Bluestone, Ben May Institute for Cancer Research, MC1089, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637. E-mail address:
3 Abbreviations used in this paper: DC, dendritic cell; mCTLA4Ig, murine CTLA4Ig.
Received for publication July 7, 1998. Accepted for publication September 10, 1998.
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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M. M. Monick, L. Samavati, N. S. Butler, M. Mohning, L. S. Powers, T. Yarovinsky, D. R. Spitz, and G. W. Hunninghake Intracellular Thiols Contribute to Th2 Function via a Positive Role in IL-4 Production J. Immunol., November 15, 2003; 171(10): 5107 - 5115. [Abstract] [Full Text] [PDF]
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 R. Hakamada-Taguchi, Y. Uehara, K. Kuribayashi, A. Numabe, K. Saito, H. Negoro, T. Fujita, T. Toyo-oka, and T. Kato Inhibition of Hydroxymethylglutaryl-Coenzyme A Reductase Reduces Th1 Development and Promotes Th2 Development Circ. Res., November 14, 2003; 93(10): 948 - 956. [Abstract] [Full Text] [PDF]
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M. Emoto, M. Miyamoto, Y. Emoto, I. Yoshizawa, V. Brinkmann, N. van Rooijen, and S. H. E. Kaufmann Highly Biased Type 1 Immune Responses in Mice Deficient in LFA-1 in Listeria monocytogenes Infection Are Caused by Elevated IL-12 Production by Granulocytes J. Immunol., October 15, 2003; 171(8): 3970 - 3976. [Abstract] [Full Text] [PDF]
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S. Gregori, N. Giarratana, S. Smiroldo, and L. Adorini Dynamics of Pathogenic and Suppressor T Cells in Autoimmune Diabetes Development J. Immunol., October 15, 2003; 171(8): 4040 - 4047. [Abstract] [Full Text] [PDF]
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K. Crawford, A. Stark, B. Kitchens, K. Sternheim, V. Pantazopoulos, E. Triantafellow, Z. Wang, B. Vasir, C. E. Larsen, D. Gabuzda, et al. CD2 engagement induces dendritic cell activation: implications for immune surveillance and T-cell activation Blood, September 1, 2003; 102(5): 1745 - 1752. [Abstract] [Full Text] [PDF]
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J. B. Chung, A. D. Wells, S. Adler, A. Jacob, L. A. Turka, and J. G. Monroe Incomplete Activation of CD4 T Cells by Antigen-Presenting Transitional Immature B Cells: Implications for Peripheral B and T Cell Responsiveness J. Immunol., August 15, 2003; 171(4): 1758 - 1767. [Abstract] [Full Text] [PDF]
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S. M. Jensen, S. L. Meijer, R. A. Kurt, W. J. Urba, H.-M. Hu, and B. A. Fox Regression of a Mammary Adenocarcinoma in STAT6-/- Mice Is Dependent on the Presence of STAT6-Reactive T Cells J. Immunol., February 15, 2003; 170(4): 2014 - 2021. [Abstract] [Full Text] [PDF]
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 R. W. Sanders, E. C. de Jong, C. E. Baldwin, J. H. N. Schuitemaker, M. L. Kapsenberg, and B. Berkhout Differential Transmission of Human Immunodeficiency Virus Type 1 by Distinct Subsets of Effector Dendritic Cells J. Virol., June 27, 2002; 76(15): 7812 - 7821. [Abstract] [Full Text] [PDF]
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C. Chirathaworn, J. E. Kohlmeier, S. A. Tibbetts, L. M. Rumsey, M. A. Chan, and S. H. Benedict Stimulation Through Intercellular Adhesion Molecule-1 Provides a Second Signal for T Cell Activation J. Immunol., June 1, 2002; 168(11): 5530 - 5537. [Abstract] [Full Text] [PDF]
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T.-L. Hsu, Y.-C. Chang, S.-J. Chen, Y.-J. Liu, A. W. Chiu, C.-C. Chio, L. Chen, and S.-L. Hsieh Modulation of Dendritic Cell Differentiation and Maturation by Decoy Receptor 3 J. Immunol., May 15, 2002; 168(10): 4846 - 4853. [Abstract] [Full Text] [PDF]
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L. Bertry-Coussot, B. Lucas, C. Danel, L. Halbwachs-Mecarelli, J.-F. Bach, L. Chatenoud, and P. Lemarchand Long-Term Reversal of Established Autoimmunity upon Transient Blockade of the LFA-1/Intercellular Adhesion Molecule-1 Pathway J. Immunol., April 1, 2002; 168(7): 3641 - 3648. [Abstract] [Full Text] [PDF]
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H. H. Smits, E. C. de Jong, J. H. N. Schuitemaker, T. B. H. Geijtenbeek, Y. van Kooyk, M. L. Kapsenberg, and E. A. Wierenga Intercellular Adhesion Molecule-1/LFA-1 Ligation Favors Human Th1 Development J. Immunol., February 15, 2002; 168(4): 1710 - 1716. [Abstract] [Full Text] [PDF]
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T. Sasada, H. Yang, and E. L. Reinherz CD2 Facilitates Differentiation of CD4 Th Cells Without Affecting Th1/Th2 Polarization J. Immunol., February 1, 2002; 168(3): 1113 - 1122. [Abstract] [Full Text] [PDF]
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 M. F. Lipscomb and B. J. Masten Dendritic Cells: Immune Regulators in Health and Disease Physiol Rev, January 1, 2002; 82(1): 97 - 130. [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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S.-h. Ogawa, G. Nagamatsu, M. Watanabe, S. Watanabe, T. Hayashi, S. Horita, K. Nitta, H. Nihei, K. Tezuka, and R. Abe Opposing Effects of Anti-Activation-Inducible Lymphocyte- Immunomodulatory Molecule/Inducible Costimulator Antibody on the Development of Acute Versus Chronic Graft-Versus-Host Disease J. Immunol., November 15, 2001; 167(10): 5741 - 5748. [Abstract] [Full Text] [PDF]
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A. Boonstra, F. J. Barrat, C. Crain, V. L. Heath, H. F. J. Savelkoul, and A. O'Garra 1{alpha},25-Dihydroxyvitamin D3 Has a Direct Effect on Naive CD4+ T Cells to Enhance the Development of Th2 Cells J. Immunol., November 1, 2001; 167(9): 4974 - 4980. [Abstract] [Full Text] [PDF]
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D. Bechard, A. Scherpereel, H. Hammad, T. Gentina, A. Tsicopoulos, M. Aumercier, J. Pestel, J.-P. Dessaint, A.-B. Tonnel, and P. Lassalle Human Endothelial-Cell Specific Molecule-1 Binds Directly to the Integrin CD11a/CD18 (LFA-1) and Blocks Binding to Intercellular Adhesion Molecule-1 J. Immunol., September 15, 2001; 167(6): 3099 - 3106. [Abstract] [Full Text] [PDF]
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 R. T. Semnani, H. Sabzevari, R. Iyer, and T. B. Nutman Filarial Antigens Impair the Function of Human Dendritic Cells during Differentiation Infect. Immun., September 1, 2001; 69(9): 5813 - 5822. [Abstract] [Full Text] [PDF]
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 K. E. WELTY-WOLF, M. S. CARRAWAY, Y.-C. T. HUANG, S. G. SIMONSON, S. P. KANTROW, T. K. KISHIMOTO, and C. A. PIANTADOSI Antibody to Intercellular Adhesion Molecule 1 (CD54) Decreases Survival and Not Lung Injury in Baboons with Sepsis Am. J. Respir. Crit. Care Med., March 1, 2001; 163(3): 665 - 673. [Abstract] [Full Text] [PDF]
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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]
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 L. H. Glimcher and K. M. Murphy Lineage commitment in the immune system: the T helper lymphocyte grows up Genes & Dev., July 15, 2000; 14(14): 1693 - 1711. [Full Text]
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A. G. A. Paul, R. van der Zee, L. S. Taams, and W. van Eden A self-hsp60 peptide acts as a partial agonist inducing expression of B7-2 on mycobacterial hsp60-specific T cells: a possible mechanism for inhibitory T cell regulation of adjuvant arthritis? Int. Immunol., July 1, 2000; 12(7): 1041 - 1050. [Abstract] [Full Text] [PDF]
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M. Whelan, M. M. Harnett, K. M. Houston, V. Patel, W. Harnett, and K. P. Rigley A Filarial Nematode-Secreted Product Signals Dendritic Cells to Acquire a Phenotype That Drives Development of Th2 Cells J. Immunol., June 15, 2000; 164(12): 6453 - 6460. [Abstract] [Full Text] [PDF]
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T. Kato and H. Nariuchi Polarization of Naive CD4+ T Cells Toward the Th1 Subset by CTLA-4 Costimulation J. Immunol., April 1, 2000; 164(7): 3554 - 3562. [Abstract] [Full Text] [PDF]
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M. R. Nicolls, M. Coulombe, H. Yang, A. Bolwerk, and R. G. Gill Anti-LFA-1 Therapy Induces Long-Term Islet Allograft Acceptance in the Absence of IFN-{gamma} or IL-4 J. Immunol., April 1, 2000; 164(7): 3627 - 3634. [Abstract] [Full Text] [PDF]
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P. R. Rogers and M. Croft CD28, Ox-40, LFA-1, and CD4 Modulation of Th1/Th2 Differentiation Is Directly Dependent on the Dose of Antigen J. Immunol., March 15, 2000; 164(6): 2955 - 2963. [Abstract] [Full Text] [PDF]
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M. Nashleanas and P. Scott Activated T Cells Induce Macrophages To Produce NO and Control Leishmania major in the Absence of Tumor Necrosis Factor Receptor p55 Infect. Immun., March 1, 2000; 68(3): 1428 - 1434. [Abstract] [Full Text] [PDF]
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S. A. Jenks and J. Miller Inhibition of IL-4 Responses After T Cell Priming in the Context of LFA-1 Costimulation Is Not Reversed by Restimulation in the Presence of CD28 Costimulation J. Immunol., January 1, 2000; 164(1): 72 - 78. [Abstract] [Full Text] [PDF]
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M. F. Bachmann, M. Barner, and M. Kopf Cd2 Sets Quantitative Thresholds in T Cell Activation J. Exp. Med., November 15, 1999; 190(10): 1383 - 1392. [Abstract] [Full Text] [PDF]
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E. S. N. Lamouse-Smith, D. S. Dougall, and S. A. McCarthy Cytokine Requirements for Production of a Novel Anti-CD8-Resistant CTL Population J. Immunol., October 15, 1999; 163(8): 4160 - 4167. [Abstract] [Full Text] [PDF]
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M. Delgado, J. Leceta, R. P. Gomariz, and D. Ganea Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide Stimulate the Induction of Th2 Responses by Up-Regulating B7.2 Expression J. Immunol., October 1, 1999; 163(7): 3629 - 3635. [Abstract] [Full Text] [PDF]
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 A. Iwasaki and B. L. Kelsall I. Mucosal dendritic cells: their specialized role in initiating T cell responses Am J Physiol Gastrointest Liver Physiol, May 1, 1999; 276(5): G1074 - G1078. [Abstract] [Full Text] [PDF]
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C. R. Luksch, O. Winqvist, M. E. Ozaki, L. Karlsson, M. R. Jackson, P. A. Peterson, and S. R. Webb Intercellular adhesion molecule-1 inhibits interleukin 4 production by naive T cells PNAS, March 16, 1999; 96(6): 3023 - 3028. [Abstract] [Full Text] [PDF]
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J. L. Ragazzo, M. E. Ozaki, L. Karlsson, P. A. Peterson, and S. R. Webb Costimulation via lymphocyte function-associated antigen 1 in the absence of CD28 ligation promotes anergy of naive CD4+ T cells PNAS, January 2, 2001; 98(1): 241 - 246. [Abstract] [Full Text] [PDF]
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