Requirement for CD28 in the Effector Phase of Allergic Airway Inflammation

Kimzey, Stephanie L.; Liu, Pingfan; Green, Jonathan M.

doi:10.4049/jimmunol.173.1.632

Cited by 21 publications

(28 citation statements)

References 34 publications

(32 reference statements)

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“…The distal proline-based motif, but not the proximal tyrosine-based motif, regulates humoral immunity in allergic airway inflammation and disease severity in EAE. We studied how the knock-in mice responded to allergic airway inflammation and EAE, two distinct CD28-dependent disease models (13,34). In the allergic airway inflammation model, only the CD28-deficient mice had a reduction in lung inflammation, as assayed by bronchoalveolar lavage cell counts and differentials and histology (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mice were immunized i.p. on days 0 and 7 with 8 g OVA absorbed to 2 mg alum (Sigma-Aldrich, St. Louis, MO) as previously described (34,35). On day 14, the mice were intranasally challenged with 50 l FIG.…”

Section: Fig 1 (A) Expression Of Cd28 On Cd4mentioning

confidence: 99%

“…The importance of CD28 in vivo is evidenced by impaired responses of CD28-deficient mice in a number of model systems, including allergic airway inflammation and experimental allergic encephalomyelitis (EAE) (13,34). In addition, the recent development of inhibitors of CD28 as effective therapeutics for autoimmune disease and transplant immunosuppression further emphasizes the critical role of this receptor in human disease (21,57).…”

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confidence: 99%

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Targeted Knock-In Mice Expressing Mutations of CD28 Reveal an Essential Pathway for Costimulation

Dodson¹,

Boomer²,

Deppong³

et al. 2009

Molecular and Cellular Biology

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Despite extensive study, the role of phosphatidylinositol 3-kinase (PI3-kinase) activation in CD28 function has been highly contentious. To definitively address this question, we generated knock-in mice expressing mutations in two critical domains of the cytoplasmic tail of CD28. Mutation of the proximal tyrosine motif interrupted PI3-kinase binding and prevented CD28-dependent phosphorylation of protein kinase B (PKB)/ Akt; however, there was no detectable effect on interleukin-2 (IL-2) secretion, expression of Bcl-X L , or on T-cell function in vivo. Furthermore, we demonstrate that signaling initiated by the C-terminal proline motif is directly responsible for tyrosine phosphorylation of phosphoinosotide-dependent kinase 1, protein kinase C, and glycogen synthase kinase 3␤, as well as contributing to threonine phosphorylation of PKB. T cells mutated in this domain were profoundly impaired in IL-2 secretion, and the mice had marked impairment of humoral responses as well as less severe disease manifestations in experimental allergic encephalomyelitis. These data demonstrate that the distal proline motif initiates a critical nonredundant signaling pathway, whereas direct activation of PI3-kinase by the proximal tyrosine motif of CD28 is not required for normal T-cell function.CD28 and T-cell receptor (TCR)-derived signals act synergistically, leading to optimal T-cell proliferation, cytokine secretion, and cell survival (for a review, see reference 32). The importance of CD28 in vivo is evidenced by impaired responses of CD28-deficient mice in a number of model systems, including allergic airway inflammation and experimental allergic encephalomyelitis (EAE) (13,34). In addition, the recent development of inhibitors of CD28 as effective therapeutics for autoimmune disease and transplant immunosuppression further emphasizes the critical role of this receptor in human disease (21,57).Despite extensive study, the biochemical mechanism(s) that mediates CD28 function remains incompletely understood. Specific motifs within the cytoplasmic tail of CD28 have been identified that trigger distinct signaling pathways. Binding and activation of Src family kinases to the distal proline motif (sequence PYAP) initiates signaling, whereas the proximal tyrosine motif (sequence YMNM) binds and activates the p85 subunit of phosphatidylinositol 3-kinase (PI3-kinase) as well as other adaptor proteins, including Grb2 and GADS (12,27,28,33,42,48,51). Studies have suggested that both motifs contribute to CD28-dependent interleukin-2 (IL-2) secretion and proliferation but that the upregulation of Bcl-X L is uniquely dependent on PI3-kinase activation by the proximal tyrosine at position 170 (11,25,43). The potential for extensive overlap between pathways initiated by each motif exists, as well as overlap between CD28 and TCR-derived signals, making it unclear as to whether CD28 initiates any critical, nonredundant signaling pathway.We generated gene-targeted knock-in mice expressing either wild-type CD28 or mutations in the proximal tyr...

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Section: Resultsmentioning

confidence: 99%

Section: Fig 1 (A) Expression Of Cd28 On Cd4mentioning

confidence: 99%

mentioning

confidence: 99%

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Targeted Knock-In Mice Expressing Mutations of CD28 Reveal an Essential Pathway for Costimulation

Dodson¹,

Boomer²,

Deppong³

et al. 2009

Molecular and Cellular Biology

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“…Mice were sensitized and challenged with OVA as described previously (11). Briefly, mice received injections i.p.…”

Section: Experimental Allergic Airway Inflammationmentioning

confidence: 99%

Cutting Edge: B and T Lymphocyte Attenuator and Programmed Death Receptor-1 Inhibitory Receptors Are Required for Termination of Acute Allergic Airway Inflammation

Deppong¹,

Juehne²,

Hurchla³

et al. 2006

The Journal of Immunology

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T cell activation is regulated by coordinate interaction of the T cell Ag receptor and costimulatory signals. Although there is considerable insight into processes that regulate the initiation of inflammation, less is known about the signals that terminate immune responses. We have examined the role of the inhibitory receptors programmed death receptor-1 and B and T lymphocyte attenuator in the regulation of allergic airway inflammation. Our results demonstrate that there is a temporally regulated expression of both the receptors and their ligands during the course of allergic airway inflammation. Following a single inhaled challenge, sensitized wild-type mice exhibit peak inflammation on day 3, which resolves by day 10. In contrast, mice deficient in the expression of programmed death receptor-1 or B and T lymphocyte attenuator have persistent inflammation out to 15 days following challenge. Thus, these receptors are critical determinants of the duration of allergic airway inflammation.

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“…In addition, treatment of mice with CTLA4Ig, a soluble inhibitor that interferes with the binding of CD28 to CD80/CD86, also prevented in vivo responses to inhaled allergen (18). Interestingly, CTLA4Ig was effective even if administered only at the time of inhaled challenge and not at sensitization, suggesting a mechanism beyond just prevention of T-cell priming (19). Furthermore, ex vivo treatment of bronchial biopsies obtained from atopic people with asthma with CTLA4Ig reduced allergen stimulated secretion of chemokines important in the recruitment of T cells to the lung (20).…”

Section: What This Study Adds To the Fieldmentioning

confidence: 98%

A Randomized Controlled Trial to Evaluate Inhibition of T-Cell Costimulation in Allergen-induced Airway Inflammation

Parulekar¹,

Boomer²,

Patterson³

et al. 2013

Am J Respir Crit Care Med

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Rationale: T lymphocytes are important in the pathogenesis of allergic asthma. Costimulation through CD28 is critical for optimal activation of T cells, and inhibition of this pathway with CTLA4Ig has been shown to be effective in preventing airway inflammation and hyperresponsiveness in animal models of asthma. Abatacept, a humanized version of CTLA4Ig, has been approved for treatment of rheumatoid arthritis, providing the opportunity to test whether inhibition of costimulation is an effective strategy to treat people with asthma. Objectives: To determine if 3 months of treatment with abatacept reduced allergen-induced airway inflammation in people with mild atopic asthma. Methods: Randomized, placebo-controlled, double-blinded study. Bronchoscopically directed segmental allergen challenge was performed on 24 subjects followed by bronchoalveolar lavage 48 hours later. Subjects were randomized 1:1 to receive abatacept or placebo, followed by a second allergen challenge protocol after 3 months of study drug. Measurements and Main Results: There was no significant reduction in allergen-induced eosinophilic inflammation in the abatacepttreated group compared with placebo (17.71% 6 17.25% vs. 46.39% 6 29.21%; P ¼ 0.26). In addition, we did not detect an effect of abatacept on FEV 1 , provocative concentration of methacholine sufficient to induce a 20% decline in FEV 1 , or asthma symptoms. Subjects treated with abatacept had an increased percentage of naive and a corresponding decrease in memory CD4 1 T cells in the blood compared with placebo. Conclusions: Inhibition of CD28-mediated costimulation with abatacept does not seem to alter the inflammatory response to segmental allergen challenge or clinical measures of asthma symptoms in people with mild atopic asthma. Clinical trial registered with ClinicalTrials.gov (NCT 00784459). Keywords: asthma; allergic inflammation; T lymphocyteAsthma and other allergic diseases are mediated by a complex inflammatory response in which the innate and adaptive immune systems have important roles (1, 2). Exposure to allergen in subjects who are atopic results in IgE-mediated activation of mast cells and basophils with the release of soluble mediators that lead to many of the acute manifestations of allergic disease (3). However, although this may initiate the allergic cascade, these events alone are not sufficient to account for the chronic inflammation characteristic of asthma.Depending on the combination of signals received, T cells may differentiate down one of several effector lineages. In the presence of IL-4, T cells develop along the Th2 lineage, which are central to allergic inflammation and are capable of secreting IL-4, IL-5, IL-9, and IL-13 (4). These cytokines orchestrate the Th2 inflammatory response, which is characterized by the recruitment of eosinophils. Although the presence and contribution of Th2 cells to airway disease in asthma is well established (5, 6), clinical trials testing agents that block IL-4, IL-5, or IL-13 have had mixed results (reviewed in [7]).T...

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Requirement for CD28 in the Effector Phase of Allergic Airway Inflammation

Cited by 21 publications

References 34 publications

Targeted Knock-In Mice Expressing Mutations of CD28 Reveal an Essential Pathway for Costimulation

Targeted Knock-In Mice Expressing Mutations of CD28 Reveal an Essential Pathway for Costimulation

Cutting Edge: B and T Lymphocyte Attenuator and Programmed Death Receptor-1 Inhibitory Receptors Are Required for Termination of Acute Allergic Airway Inflammation

A Randomized Controlled Trial to Evaluate Inhibition of T-Cell Costimulation in Allergen-induced Airway Inflammation

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