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Abstract |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Airway inflammation after inhaled allergen exposure requires the recruitment, activation, and differentiation of antigen-specific T cells into T helper (Th) 2 effector cells. These processes are regulated not only by antigen engagement of the T-cell receptor, but also by specific accessory molecules on the surface of the T cell. We examined how the balance of signals derived through the CD28 and cytotoxic T-lymphocyte antigen (CTLA) 4 receptors modulate the outcome of inhaled antigen exposure in a murine model of allergic airway inflammation. Mice deficient in CD28 have defective Th2 cell development and failed to develop inflammation after sensitization and inhaled challenge with ovalbumin. Prevention of B7-CTLA4 interactions in CD28-deficient mice restored lymphocyte but not eosinophil recruitment to the airway. Analysis of cytokine gene expression revealed that T cells from CD28-deficient mice failed to differentiate into Th2 cells in either the presence or absence of B7-dependent signals, and therefore did not recruit eosinophils to the airway. Thus, the processes of T-cell recruitment to the airway and T-cell differentiation have distinct requirements for signals mediated through the CD28 and CTLA4 receptors, demonstrating that these receptors are important regulatory components in the development of allergic airway inflammation.
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Introduction |
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Introduction
Materials and Methods
Results
Discussion
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Asthma is characterized by acute and chronic airway inflammation. Allergen exposure in susceptible individuals results in the recruitment and activation of inflammatory cells, which leads to bronchoconstriction and further perpetuation of the inflammatory response. Central to this process is the T lymphocyte. T cells in atopic asthma are predominantly a T helper (Th) 2 phenotype, characterized by the secretion of interleukin (IL)-4, -5, and -13 (1, 2). These cytokines promote the recruitment and survival of eosinophils as well as production of immunoglobulin (Ig) E. In addition, IL-13 has been shown to mediate many of the cardinal features of asthma in a murine model of the disease (3, 4). Thus, T-cell recruitment and differentiation are critical elements in the evolution of the asthmatic state. The factors that regulate these aspects of T-cell function are incompletely understood, but may include engagement of specific accessory molecules on the T cell.
The encounter of a T cell with antigen triggers a complex series of biochemical and cellular responses leading to cell growth and differentiation. In addition to engagement of the T-cell receptor (TCR), other proteins on the surface of the lymphocyte are important in determining the outcome of an encounter with antigen (5). Due to their ability to enhance the activation of T cells, these proteins have been termed costimulatory receptors. Although several proteins have been identified as costimulatory receptors, one of the most important is CD28. CD28 is expressed on naive T cells; and engagement of CD28 by its ligands, B7-1 (CD80) or B7-2 (CD86), in conjunction with TCR ligation, positively regulates multiple aspects of T-cell function, including proliferation and cytokine secretion (6). The CD28 homolog cytotoxic T-lymphocyte antigen (CTLA) 4 (CD152) is expressed on activated T cells. CTLA4 also binds B7-1 and B7-2, but in contrast to CD28, it is a negative regulatory molecule capable of inhibiting T-cell responses (7). Thus, the process of T-cell activation involves not only engagement of the TCR by antigen, but also the integration of positive and negative signals delivered through B7 interactions with CD28 and/or CTLA4.
Previous studies have suggested a role for CD28 in the development of airway inflammation (8). In a murine model of asthma, examination of CD28-deficient mice or treatment of wild-type animals with a soluble reagent, CTLA4Ig, that prevents B7 from binding either CD28 or CTLA4 abrogated both airway inflammation and hyperresponsiveness, suggesting a critical role for this pathway in the pathogenesis of the disease. Thus, the manipulation of T-cell costimulation may be an effective strategy in the treatment of airway inflammation. However, the respective contributions of CD28 and CTLA4 in the regulation of this response have not been determined.
We have examined the role of CD28 and CTLA4 in
T-cell recruitment and differentiation in a murine model of
allergic airway inflammation. Mice genetically deficient in
CD28 expression were subjected to sensitization and inhaled challenge with ovalbumin (OVA). CD28-deficient
(CD28 
/) mice did not manifest airway inflammation in
response to challenge, despite evidence of systemic sensitization. This was due to a failure in T-cell recruitment and
defective Th2 cell development. Prevention of CTLA4 engagement by blockade of B7-1 and B7-2 in CD28-deficient
mice restored lymphocyte recruitment to the airway but
did not result in tissue eosinophilia, Ig isotype switching, or
Th2 cytokine secretion. Therefore, the regulation of T-cell
recruitment to the airway and Th2 differentiation differ in
their requirement for signaling through CD28 and CTLA4.
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Materials and Methods |
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Abstract
Introduction
Materials and Methods
Results
Discussion
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Mice
CD28-deficient mice (13) backbred into the C57BL/6 background were maintained in specific pathogen-free facilities at Washington University School of Medicine. Wild-type C57BL/6J mice were purchased from Jackson Laboratories (Bar Harbor, ME).
Induction and Analysis of Airway Inflammation
Wild-type C57BL/6 or CD28-deficient mice were injected intraperitoneally with 8 µg OVA adsorbed to 2 mg Alum (Sigma, St. Louis, MO) in 0.5 ml sterile phosphate-buffered saline (PBS) on Days 0 and 7. Control mice (naive) were injected with Alum in PBS alone. On Day 14 the mice were challenged by ultrasonic nebulization of a solution of 1% (wt/vol) OVA in PBS delivered by a clinical nebulizer (DeVilbiss Ultra-Neb 99) in the morning and again in the afternoon. In some experiments, mice received murine CTLA4Ig (50 µg/mouse; provided by M. Collins, Genetics Institute, Cambridge, MA) or a control Ig (control murine IgG2a; PharMingen, San Diego, CA) intraperitoneally immediately before sensitization and challenge. At 72 h after challenge the mice were killed by lethal injection with a mixture of Ketamine/Xylazine and specimens were collected for analysis. Blood was collected by cardiac puncture for analysis of Ig titers. The lungs were flushed of blood by injecting the right and left ventricles with PBS. Bronchoalveolar lavage (BAL) was performed by cannulation of the trachea with a 22-gauge catheter and sequential lavages with 0.8 ml of PBS containing 1% bovine serum albumin (BSA). After lavage the lungs were inflation fixed with 10% neutral buffered formalin, fixed overnight, and progressively dehydrated, and transferred to 70% ethanol. Where indicated, frozen sections were obtained from lungs injected with a mixture of 50% Tissue-Tek OCT compound (Sakura Finetek, Torrance, CA) in PBS and frozen on dry ice. Formalin-fixed tissue was processed by the histology core laboratory for hematoxylin and eosin staining. Frozen tissue was cryostat-sectioned and fixed in acetone. Eosinophils were stained by assaying for the presence of cyanide-resistant peroxidase activity. Acetone-fixed sections were incubated for 10 min in a diaminobenzidine (Sigma-fast) solution containing 1.6 mg/ml potassium cyanide. The slides were then rinsed and counterstained with methyl green.
Enzyme-Linked Immunosorbent Assay
OVA-specific Ig titers were determined by enzyme-linked immunosorbent assay (ELISA). In brief, Immulon 2 microtiter plates (Dynatech Laboratories, Chantilly, VA) were coated overnight with a solution of OVA (20 µg/ml) in 0.1 M NaHCO3, pH 8.2. The wells were blocked with PBS containing 0.2 % Tween-20 and 2% BSA (Sigma) and incubated with serial dilutions of serum from individual control or sensitized mice. Detection with p-nitrophenyl phosphate was performed after incubation with an isotype-specific anti-Ig monoclonal antibody (mAb) (Southern Biotechnologies, Birmingham, AL) conjugated to alkaline phosphatase. The plates were allowed to develop and absorbance at 405 nm was determined on a microtiter plate reader. OVA-specific IgE was determined by coating Immulon 2 plates with antimurine IgE mAb (PharMingen) followed by incubation with immune sera. Detection was performed by subsequent incubation with biotinylated OVA and avidin-biotin AP reagent (Vector Laboratories, Burlingame, CA).
Ribonuclease Protection Assay
Splenocytes from naive or sensitized wild-type or CD28-deficient mice were stimulated in vitro for 24 h with 100 µg/ml OVA. Total cellular RNA was isolated using Trizol reagent (Life Technologies, Grand Island, NY) according to the manufacturer's directions. Cytokine messenger RNA (mRNA) levels were determined using the Riboquant kit (PharMingen) and the mCK-1 probe set according to the manufacturer's directions.
Reverse Transcriptase/Polymerase Chain Reaction
Total cellular RNA was isolated from whole lung tissue using Trizol reagent. The RNA was reverse transcribed from 1 µg RNA using Retro-Script (Ambion, Austin, TX) and polymerase chain reaction (PCR) was performed on 2 µl complementary DNA using standard primers and conditions as previously described (14). PCR products were visualized by ethidium bromide staining after agarose gel electrophoresis.
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Results |
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Materials and Methods
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Blockade of B7 Restores Inflammation in CD28-Deficient Mice
To determine the role of CD28 and CTLA4 in a murine model of allergic airway inflammation we examined the response of wild-type and CD28-deficient mice to inhaled antigen challenge. Mice were systemically sensitized to OVA followed by exposure to aerosolized OVA. Control mice were not sensitized (naive) but did receive the inhaled challenge. Samples were collected for analysis 72 h later. Examination of the BAL fluid (BALF) from wild-type mice revealed an influx of inflammatory cells including eosinophils, lymphocytes, and neutrophils after inhaled challenge of sensitized mice (Figure 1). In contrast, the BALF from CD28-deficient mice was similar in both cell number and composition to that of naive mice, consisting predominantly of alveolar macrophages. Histologic analysis demonstrated marked perivascular and peribronchial inflammatory cell infiltration in wild-type but not CD28-deficient mice (Figure 2). Staining for cyanide-resistant peroxidase confirmed the presence of tissue eosinophils only in specimens from wild-type mice. (Figures 2C and 2F).
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To determine whether the failure of CD28-deficient mice to respond to inhaled antigen challenge was due exclusively to the lack of a positive signal from CD28, or whether an unopposed negative signal through CTLA4 was inhibiting the T-cell response, we treated mice with CTLA4Ig during sensitization and challenge with OVA (Figure 3). CTLA4Ig binds both B7-1 and B7-2 and prevents either from interaction with CD28 or CTLA4. Treatment of wild-type mice with CTLA4Ig prevented the development of airway inflammation as assessed by BAL (Figures 3A and 3B) and histology (Figure 3C). In contrast, when given to CD28-deficient mice, CTLA4Ig restored inflammatory cell recruitment to the airway (Figures 3A and 3C). However, examination of the cellular infiltrate revealed that although mononuclear cells were present, eosinophils were not recruited to the airways (Figures 3B and 3C). Thus, B7 engagement of CTLA4 appears to suppress leukocyte recruitment to the lung, but prevention of CTLA4 signaling resulted in a qualitatively distinct inflammatory response in the absence of CD28 signaling.
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CD28 Is Required for Antigen-Induced Th2 Cytokine Expression
Consistent with the eosinophilic nature of the inflammatory cell infiltrate, C57Bl/6 mice immunized and challenged
with OVA developed a Th2-type response characterized by
IL-4- and IL-5-secreting T cells, as well as OVA-specific
Ig isotypes IgG1 and IgE. Examination of cytokine mRNA
isolated from the splenocytes of sensitized mice revealed
induction of IL-4, IL-5, IL-13, and IL-2 gene expression in
CD28 +/+ but not CD28-deficient mice (Figure 4A). T
cells from naive CD28-deficient mice had a cytokine profile similar to naive wild type mice (data not shown). IL-2
gene expression was markedly impaired, consistent with
the known role of CD28 as regulator of IL-2 mRNA levels (15). Wild-type mice also demonstrated an increase in
interferon (IFN)-
mRNA expression, suggesting a potential role for Th1 cytokines in this response.
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The lymphocytic tissue infiltrate accompanied by the
failure to recruit eosinophils in CTLA4Ig-treated CD28/
mice suggested that whereas blockade of B7-CTLA4 interactions restored cell recruitment to the airway, Th2 cell
differentiation might not have been similarly affected. To
test this we examined the cytokine profiles of splenocytes and whole lung preparations from control or CTLA4Ig-treated mice (Figures 4A and 4B). Despite its ability to restore inflammatory cell recruitment to the lung, CTLA4Ig
treatment did not result in the expression of mRNA for
Th2 cytokines in either the spleen or inflammatory cells of
the lung of CD28-deficient mice (Figure 4). Examination
of the cytokine profile of cells in the lung by reverse transcriptase (RT)-PCR revealed expression of IL-4 only in
the control-treated wild-type mice (Figure 4B).
To confirm the results obtained by examination of cytokine mRNA levels, we determined the Ig profile of wild-type and CD28-deficient mice sensitized and challenged with OVA either alone or after treatment with CTLA4Ig. Wild-type mice had elevated levels of OVA-specific IgG1 and IgE, consistent with a Th2 response. CD28-deficient mice did not mount an antibody response to OVA. After treatment with CTLA4Ig, OVA-specific IgG1 or IgG2a was still not detected in the CD28-deficient mice, consistent with defective Th2 cell development (Figure 5B).
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The manipulation of costimulatory molecules has been shown to influence a variety of disease models. Blockade of B7 in wild-type mice results in delayed allograft rejection and impaired T-dependent antibody responses (16- 18). Similarly, CD28-deficient mice have impaired in vivo and in vitro T-cell dependent responses. The decreased responses of CD28-deficient mice, or of wild-type mice treated with soluble B7 inhibitors, has been thought to be primarily due to the loss of a positive signal through CD28 (19). However, recent work has suggested that in fact it may be due to unmasking of a negative signal through CTLA4 (20, 21).
We have examined the role of CD28 and CTLA4 in a
murine model of allergic airway inflammation. CD28-deficient mice did not develop inflammation in response to sensitization and inhaled challenge with OVA. Splenocytes
from wild-type or CD28-deficient mice showed evidence of
sensitization as determined by in vitro proliferation to OVA
(data not shown), suggesting that the immunization protocol led to T-cell activation and clonal expansion. Despite this, the cells did differentiate normally into Th2 effector
cells. Treatment of CD28-deficient mice with CTLA4Ig restored the recruitment of inflammatory cells to the lung,
suggesting that engagement of CTLA4 by its ligand B7 prevented inflammation in the absence of CD28. However, the
inflammatory infiltrate lacked eosinophils; thus, the inflammation observed in CTLA4Ig-treated CD28 / mice was
qualitatively different from that seen in wild-type mice.
The mechanism by which lymphocyte recruitment to the airway is restored in CD28-deficient mice after CTLA4Ig treatment is not clear, but may involve the regulation of chemokine and chemokine receptor expression by CD28 and CTLA4. Treatment with CTLA4Ig may alter the subset of chemokine receptors expressed by either wild-type or CD28-deficient mice after allergen challenge, allowing for selective recruitment to the airway. In support of this, preliminary data in our lab have demonstrated that T cells from CD28-deficient mice have an altered expression pattern of both chemokine and chemokine receptor expression after antigen activation (Burr and Green, unpublished data). It has also been shown that blockade of costimulation prevented allergen-induced chemotaxis, as well as secretion of IL-16 and RANTES in bronchial biopsy tissue obtained from asthmatics (22).
The response of CD28 +/+ mice to OVA is characterized by development of Th2 cells that secrete IL-4 and IL-5
and promote Ig isotype switching to IgG1 and IgE (23).
Splenocytes from wild-type mice sensitized to OVA demonstrated induction of IL-4, IL-5, and IL-13 gene expression, as
well as increased levels of IL-2 and IFN-. In contrast, sensitization of CD28-deficient mice did not induce expression of
any cytokines above levels observed in naive mice. Consistent with this, we observed no OVA-specific IgG1 and IgE
in the sera of immunized CD28-deficient mice. Thus, in
agreement with Padrid and colleagues (11) and Van Oosterhout and associates (24), our results suggest that CD28 is required for normal Th2 cell differentiation and function in response to OVA. Recent reports have suggested that IL-13
may be critical in the induction of airway inflammation and
hyperresponsiveness (3, 4). CD28-deficient mice also failed
to induce IL-13 mRNA expression in response to OVA sensitization. Thus, the regulation of IL-13 by CD28 may represent a novel mechanism by which costimulation modulates
the development of airway inflammation.
Examination of Th-cell phenotype in CTLA4Ig-treated
CD28-deficient mice revealed that despite prevention of
CTLA4 signaling, Th2 cytokine gene expression was not
restored in the absence of CD28. Consistent with this result, CTLA4Ig did not restore Ig isotype switching to IgG1
in CD28-deficient mice. Thus, although CTLA4 appeared
to inhibit lymphocyte recruitment to the lung, prevention
of its engagement by B7 did not allow for normal T-cell differentiation. Examination of allograft rejection in CD28-deficient mice has suggested that blockade of B7-CTLA4
interactions can restore T-cell function such that normal
graft rejection occurs in the absence of CD28 (20). This
suggests that Th1 development may occur independent of
CD28 if CTLA4 signaling is inhibited. Our data demonstrate that the requirement for CD28 is more stringent in the development of a Th2 response. Recent work indicates that CTLA4 may directly influence both Th1 and
Th2 cell development (25). CTLA4 ligation inhibits IL-2
and IFN- secretion in the absence of CD28, but when
CD28 is present it may be dominant over CTLA4 (21).
The observation that CTLA4Ig blocks inflammation in wild-type mice yet restores it in CD28-deficient mice is somewhat paradoxical in that in both situations all B7-dependent responses should be inhibited; however, it is consistent in our studies and in previous reports (20). A potential explanation is that CTLA4 may not be as effectively blocked in the wild-type mouse as in the CD28-deficient mouse because CD28 costimulation is a potent inducer of CTLA4 expression (26).
Previous studies on the role of costimulation in airway inflammation have demonstrated a requirement for B7-mediated costimulation for inflammatory cell recruitment and airway hyperreactivity. We expanded upon this by examining the contributions of CD28 and CTLA4 in this complex in vivo response. Our data suggest that CTLA4 can inhibit not only the activation of the T cells but also their ability to be recruited to the site of antigen challenge. However, CD28-mediated events are necessary for these cells to differentiate into Th2 effector cells. Therefore, the molecular events that regulate the processes of T-cell recruitment and Th-cell differentiation have distinct requirements for CD28- and CTLA4-mediated signals.
How CTLA4 functions remains controversial. Some studies have demonstrated an interaction of CTLA4 with protein tyrosine phosphatases that may terminate TCR-mediated signals (27, 28). Alternatively, CTLA4 may sequester B7 and prevent its interaction with CD28. Interestingly, truncation of most of the cytoplasmic tail of CTLA4 did not affect its ability to inhibit T-cell activation (29). Our data would suggest that sequestration of B7 from CD28 cannot be the only mechanism by which CTLA4 functions.
Coreceptor modulation of Th-cell differentiation has been an area of considerable interest. CD28 has been demonstrated to play an important role in several disease models characterized by both Th1- and Th2-cell development. In some instances, discordant results have been obtained in treatment of wild-type mice with CTLA4Ig and in examination of CD28-deficient mice (30). Although it is apparent that CD28 engagement is not an absolute prerequisite to Th2-cell development, CD28-mediated events are capable of promoting the differentiation and/or the survival of Th2-cells. The mechanism by which CD28 promotes Th2-cell development is unclear. However, a recent study of Itk-deficient mice may provide some insight. Itk has been implicated in CD28 signaling, and it appears that this kinase plays a critical role in Th2- but not Th1-cell development (34). Further studies into the mechanism by which CD28 and CTLA4 modulate T-cell activation and differentiation may allow for manipulation of these receptors or their signal transduction pathways and provide for novel opportunities to influence the outcome of immune responses in vivo.
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Address correspondence to: Jonathan M. Green, M.D., Washington University School of Medicine, 660 S. Euclid Ave., Box 8052, St. Louis, MO 63110. E-mail: greenj{at}msnotes.wustl.edu
(Received in original form September 15, 2000 and in revised form December 12, 2000).
Abbreviations: bronchoalveolar lavage, BAL; BAL fluid, BALF; CD28-deficient, CD28/; cytotoxic T-lymphocyte antigen, CTLA; interferon,
IFN; immunoglobulin, Ig; interleukin, IL; messenger RNA, mRNA; ovalbumin, OVA; phosphate-buffered saline, PBS; polymerase chain reaction,
PCR; T-cell receptor, TCR; T helper, Th.
Acknowledgments: The authors thank David Chaplin, Robert Arch, and Dwight Look for helpful discussion and critical review of the manuscript, and also thank Mary Collins for providing the CTLA4Ig used in these studies. One author (J.M.G.) is supported in part by NIH grants K08HL58444 and R01HL62683 and a grant from the American Lung Association of Eastern Missouri.
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References |
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References
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1. Corrigan, C. J., and A. B. Kay. 1992. T cells and eosinophils in the pathogenesis of asthma. Immunol. Today 13: 501-507 [Medline].
2. Seder, R. A., and W. E. Paul. 1994. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu. Rev. Immunol. 12: 635-673 [Medline].
3.
Grunig, G.,
M. Warnock,
A. E. Wakil,
R. Venkayya,
F. Brombacher,
D. M. Rennick,
D. Sheppard,
M. Mohrs,
D. D. Donaldson,
R. M. Locksley, and
D. B. Corry.
1998.
Requirement for IL-13 independently of IL-4 in experimental asthma.
Science
282:
2261-2263
4.
Wills-Karp, M.,
J. Luyimbazi,
X. Xu,
B. Schofield,
T. Y. Neben,
C. L. Karp, and
D. D. Donaldson.
1998.
Interleukin-13: central mediator of allergic
asthma.
Science
282:
2258-2261
5.
Schwartz, R. H..
1990.
A cell culture model for T lymphocyte clonal anergy.
Science
248:
1349-1356
6. June, C. H., J. A. Bluestone, L. M. Nadler, and C. B. Thompson. 1994. The B7 and CD28 receptor families. Immunol. Today 15: 321-330 [Medline].
7. Walunas, T. L., D. J. Lenschow, C. Y. Bakker, P. S. Linsley, G. J. Freeman, J. M. Green, C. B. Thompson, and J. A. Bluestone. 1994. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1: 405-413 [Medline].
8. Keane-Myers, A., W. C. Gause, P. S. Linsley, S. J. Chen, and M. Wills-Karp. 1997. B7-CD28/CTLA-4 costimulatory pathways are required for the development of T helper cell 2-mediated allergic airway responses to inhaled antigens. J. Immunol. 158: 2042-2049 [Abstract].
9. Krinzman, S. J., G. T. De Sanctis, M. Cernadas, D. Mark, Y. Wang, J. Listman, L. Kobzik, C. Donovan, K. Nassr, I. Katona, D. C. Christiani, D. L. Perkins, and P. W. Finn. 1996. Inhibition of T cell costimulation abrogates airway hyperresponsiveness in a murine model. J. Clin. Invest. 98: 2693-2699 [Medline].
10.
Harris, N.,
C. Campbell,
G. Le Gros, and
F. Ronchese.
1997.
Blockade of
CD28/B7 co-stimulation by mCTLA4-H1 inhibits antigen-induced lung
eosinophilia but not Th2 cell development or recruitment in the lung.
Eur.
J. Immunol.
27:
155-161
[Medline].
11.
Padrid, P. A.,
M. Mathur,
X. T. Li,
K. Hermann,
Y. M. Qin,
A. Cattamanchi,
J. Weinstock,
D. Elliot,
A. I. Sperling, and
J. A. Bluestone.
1998.
CTLA4Ig inhibits airway eosinophilia and hyperresponsiveness by regulating the development of Th1/Th2 subsets in a murine model of asthma.
Am. J. Respir. Cell Mol. Biol.
18:
453-462
12.
Mathur, M.,
K. Herrmann,
Y. Qin,
F. Gulmen,
X. Li,
R. Krimins,
J. Weinstock,
D. Elliott,
J. A. Bluestone, and
P. Padrid.
1999.
CD28 interactions
with either CD80 or CD86 are sufficient to induce allergic airway inflammation in mice.
Am. J. Respir. Cell Mol. Biol.
21:
498-509
13.
Shahinian, A.,
K. Pfeffer,
K. P. Lee,
T. M. Kündig,
K. Kishihara,
A. Wakeham,
K. Kawai,
P. S. Ohashi,
C. B. Thompson, and
T. W. Mak.
1993.
Differential T cell costimulatory requirements in CD28-deficient mice.
Science
261:
609-612
14. Reiner, S. L., S. Zheng, D. B. Corry, and R. M. Locksley. 1993. Constructing polycompetitor cDNAs for quantitative PCR. J. Immunol. Methods 165: 37-46 [Medline].
15.
Lindsten, T.,
C. H. June,
J. A. Ledbetter,
G. Stella, and
C. B. Thompson.
1989.
Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway.
Science
244:
339-343
16.
Linsley, P. S.,
P. M. Wallace,
J. Johnson,
M. G. Gibson,
J. L. Greene,
J. A. Ledbetter,
C. Singh, and
M. A. Tepper.
1992.
Immunosuppression in vivo
by the soluble form of the CTLA-4 T cell activation molecule.
Science
257:
792-795
17.
Lenschow, D. J.,
Y. Zeng,
J. R. Thistlethwaite,
A. Montag,
W. Brady,
M. G. Gibson,
P. S. Linsley, and
J. A. Bluestone.
1992.
Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig.
Science
257:
789-792
18.
Turka, L. A.,
P. S. Linsley,
H. Lin,
W. Brady,
J. M. Leiden,
R.-Q. Wei,
M. L. Gibson,
X.-G. Zheng,
S. Myrdal,
D. Gordon,
T. Bailey,
S. F. Bolling, and
C. B. Thompson.
1992.
T-cell activation by the CD28 ligand B7 is required
for cardiac allograft rejection in vivo.
Proc. Natl. Acad. Sci. USA
89:
11102-11105
19. Green, J. M., P. J. Noel, A. I. Sperling, T. L. Walunas, G. S. Gray, J. A. Bluestone, and C. B. Thompson. 1994. Absence of B7-dependent responses in CD28-deficient mice. Immunity 1: 501-508 [Medline].
20.
Lin, H.,
J. C. Rathmell,
G. S. Gray,
C. B. Thompson,
J. M. Leiden, and
M. L. Alegre.
1998.
Cytotoxic T lymphocyte antigen 4 (CTLA4) blockade
accelerates the acute rejection of cardiac allografts in CD28-deficient mice:
CTLA4 can function independently of CD28.
J. Exp. Med.
188:
199-204
21.
Fallarino, F.,
P. E. Fields, and
T. F. Gajewski.
1998.
B7-1 engagement of cytotoxic T lymphocyte antigen 4 inhibits T cell activation in the absence of
CD28.
J. Exp. Med.
188:
205-210
22.
Hidi, R.,
V. Riches,
M. Al-Ali,
W. W. Cruikshank,
D. M. Center,
S. T. Holgate, and
R. Djukanovic.
2000.
Role of B7-CD28/CTLA-4 costimulation
and NF-kappa B in allergen-induced T cell chemotaxis by IL-16 and
RANTES.
J. Immunol.
164:
412-418
23. Kung, T. T., H. Jones, G. K. Adams III, S. P. Umland, W. Kreutner, R. W. Egan, R. W. Chapman, and A. S. Watnick. 1994. Characterization of a murine model of allergic pulmonary inflammation. Int. Arch. Allergy Immunol. 105: 83-90 [Medline].
24.
Van Oosterhout, A. J.,
C. L. Hofstra,
R. Shields,
B. Chan,
I. Van Ark,
P. M. Jardieu, and
F. P. Nijkamp.
1997.
Murine CTLA4-IgG treatment inhibits
airway eosinophilia and hyperresponsiveness and attenuates IgE upregulation in a murine model of allergic asthma.
Am. J. Respir. Cell Mol. Biol.
17:
386-392
25.
Oosterwegel, M. A.,
D. A. Mandelbrot,
S. D. Boyd,
R. B. Lorsbach,
D. Y. Jarrett,
A. K. Abbas, and
A. H. Sharpe.
1999.
The role of CTLA-4 in regulating Th2 differentiation.
J. Immunol.
163:
2634-2639
26. Lindsten, T., K. P. Lee, E. S. Harris, B. Petryniak, N. Craighead, P. J. Reynolds, D. B. Lombard, G. J. Freeman, L. M. Nadler, G. S. Gray, et al . 1993. Characterization of CTLA-4 structure and expression on human T cells. J. Immunol. 151: 3489-3499 [Abstract].
27.
Lee, K. M.,
E. Chuang,
M. Griffin,
R. Khattri,
D. K. Hong,
W. Zhang,
D. Straus,
L. E. Samelson,
C. B. Thompson, and
J. A. Bluestone.
1998.
Molecular basis of T cell inactivation by CTLA-4.
Science
282:
2263-2266
28. Marengere, L. E., P. Waterhouse, G. S. Duncan, H. W. Mittrucker, G. S. Feng, and T. W. Mak. 1996. Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4. Science 272: 1170-1173 [Abstract].
29.
Nakaseko, C.,
S. Miyatake,
T. Iida,
S. Hara,
R. Abe,
H. Ohno,
Y. Saito, and
T. Saito.
1999.
Cytotoxic T lymphocyte antigen 4 (CTLA-4) engagement
delivers an inhibitory signal through the membrane-proximal region in the
absence of the tyrosine motif in the cytoplasmic tail.
J. Exp. Med.
190:
765-774
30. Corry, D. B., S. L. Reiner, P. S. Linsley, and R. M. Locksley. 1994. Differential effects of blockade of CD28-B7 on the development of Th1 or Th2 effector cells in experimental leishmaniasis. J. Immunol. 153: 4142-4148 [Abstract].
31.
Brown, D. R.,
J. M. Green,
N. H. Moskowitz,
M. Davis,
C. B. Thompson, and
S. L. Reiner.
1996.
Limited role of CD28-mediated signals in T helper
cell subset differentiation.
J. Exp. Med.
184:
803-810
32. Gause, W. C., J. F. Urban, P. Linsley, and P. Lu. 1995. Role of B7 signaling in the differentiation of naive CD4+ T cells to effector interleukin-4-producing T helper cells. Immunol. Res. 14: 176-188 [Medline].
33. Gause, W. C., S. J. Chen, R. J. Greenwald, M. J. Halvorson, P. Lu, X. D. Zhou, S. C. Morris, K. P. Lee, C. H. June, F. D. Finkelman, J. F. Urban, and R. Abe. 1997. CD28 dependence of T cell differentiation to IL-4 production varies with the particular type 2 immune response. J. Immunol. 158: 4082-4087 [Abstract].
34. Fowell, D. J., K. Shinkai, X. C. Liao, A. M. Beebe, R. L. Coffman, D. R. Littman, and R. M. Locksley. 1999. Impaired NFATc translocation and failure of Th2 development in Itk-deficient CD4+ T cells. Immunity 11: 399-409 [Medline].
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