Antigen-specific effector CD8 T cells regulate allergic responses via IFN-? and dendritic cell function (original) (raw)
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Specific CD8 T Cells in IgE-mediated Allergy Correlate with Allergen Dose and Allergic Phenotype
American Journal of Respiratory and Critical Care Medicine, 2010
Rationale: Studies in humans and rodents have indicated a causative role for CD8 1 T cells in IgE-mediated allergic inflammation, but their function is still controversial. Objectives: To analyze the role of allergen-specific CD8 1 T cells during the development of allergic airway inflammation in two parallel but diverging outcome models. Methods: We used H2-Kb SIINFEKL (OVA 257-264 ) multimers to analyze induction, natural distribution, and phenotype of allergen-specific CD8 1 T cells in a murine C57BL/6 model of ovalbumin (OVA)-induced allergic airway inflammation using low-dose or high-dose OVA sensitization. Measurements and Main Results: The low-dose protocol was characterized by a significant induction of total and OVA-specific IgE, eosinophilic airway inflammation, IL-4 levels in bronchoalveolar lavage fluid. And significant alterations in lung function. The high dose protocol was characterized by a significant reduction of the allergic phenotype. Using OVA 257-264 H2-Kb multimers, we observed lung and airway infiltrating OVA-specific CD8 1 T cells showing an effector/effectormemory phenotype. The high-dose protocol caused significantly higher infiltration of allergen-specific CD8 1 cells to the airways and enhanced their cytotoxicity. Adoptive transfer with CD8 1 T cells from transgenic OT-I mice to TAP1 2/2 or wild-type mice showed their migration to the lungs and TAP1-dependent proliferation after OVAaerosol exposure. TAP1 2/2 mice defective in CD8 1 T cells showed exacerbated symptoms in the low-dose sensitization model. Conclusions: Allergen-specific CD8 1 T cells seem to protect from allergic inflammation in the lungs. Their number, which is dependent on the sensitization dose, appears to be a critical predictor for the severity of the allergic phenotype.
Immunology, 2007
We have previously shown that CD8 + cd T cells decrease late allergic airway responses, airway eosinophilia, T helper 2 cytokine expression and increase interferon-c (IFN-c) expression. We hypothesized that the effects of CD8 + cd T cells were IFN-c mediated. Brown Norway rats were sensitized to ovalbumin on day 1. Cervical lymph node CD8 + cd T cells from sensitized animals were treated with antisense oligodeoxynucleotide (5 lmol/l) to inhibit IFN-c synthesis or control oligodeoxynucleotide and 3Á5 • 10 4 CD8 + cd T cells were injected intraperitoneally into sensitized recipients on day 13. Rats were challenged with aerosolized ovalbumin on day 15 and lung resistance was monitored over an 8 hr period, after which bronchoalveolar lavage was performed. Control oligodeoxynucleotide treated cd T cells decreased late airway responses and eosinophilia in bronchoalveolar lavage. There was a complete recovery of late airway responses and a partial recovery of airway eosinophilia in recipients of antisense oligodeoxynucleotide treated cells. Macrophage ingestion of eosinophils was frequent in rats administered cdT cells but reduced in recipients of antisense oligodeoxynucleotide treated cells. These results indicate that CD8 + cd T cells inhibit late airway responses and airway eosinophilia through the secretion of IFN-c. Defective or altered cd T-cell function may account for some forms of allergic asthma.
Immunology, 2007
We have previously shown that CD8 + cd T cells decrease late allergic airway responses, airway eosinophilia, T helper 2 cytokine expression and increase interferon-c (IFN-c) expression. We hypothesized that the effects of CD8 + cd T cells were IFN-c mediated. Brown Norway rats were sensitized to ovalbumin on day 1. Cervical lymph node CD8 + cd T cells from sensitized animals were treated with antisense oligodeoxynucleotide (5 lmol/l) to inhibit IFN-c synthesis or control oligodeoxynucleotide and 3Á5 • 10 4 CD8 + cd T cells were injected intraperitoneally into sensitized recipients on day 13. Rats were challenged with aerosolized ovalbumin on day 15 and lung resistance was monitored over an 8 hr period, after which bronchoalveolar lavage was performed. Control oligodeoxynucleotide treated cd T cells decreased late airway responses and eosinophilia in bronchoalveolar lavage. There was a complete recovery of late airway responses and a partial recovery of airway eosinophilia in recipients of antisense oligodeoxynucleotide treated cells. Macrophage ingestion of eosinophils was frequent in rats administered cdT cells but reduced in recipients of antisense oligodeoxynucleotide treated cells. These results indicate that CD8 + cd T cells inhibit late airway responses and airway eosinophilia through the secretion of IFN-c. Defective or altered cd T-cell function may account for some forms of allergic asthma.
Journal of Allergy and Clinical Immunology, 1996
CD8+ (OX-8+) T cells may suppress airway inflammation and airway responsiveness after allergen challenge. We studied the effects of depletion of OX-8+ T cells on allergen-induced lung eosinophilia and airway responsiveness in the Sprague-Dawley rat. Sprague-Dawley rats were sensitized to ovalbumin and challenged by aerosol 14 days later. Test animals received either low-dose (2 mg, n = 9) or high-dose (3 mg, n = 7) OX-8 monoclonal antibody (mAb), whereas controls (n = 8) received BALB/c ascites fluid. A fourth group of animals (n = 10) was not sensitized to ovalbumin and also received ascites fluid. Twenty-four hours after ovalbumin challenge, responsiveness to methacholine was measured, and lung inflammation was assessed in the large airways and small airways and parenchyma. Circulating and airway CD8+ T cells were decreased by OX-8 mAb administration with greatest changes in animals treated with high-dose OX-8 mAb compared with controls (blood: 1.0% +/- 3.6% vs 18.7% +/- 3.9%, p < 0.05); (large airways: 2.5% +/- 1.2% vs 13.8% +/- 1.2%, p < 0.05). Ovalbumin challenge resulted in increases in macrophages and neutrophils in the small airways and parenchyma of sensitized compared with unsensitized rats (p < 0.05). High-dose OX-8 mAb further increased total leukocytes, attributable to increases in neutrophils and eosinophils, retrieved from the large airways and small airways and parenchyma compared with other groups (p < 0.05). Airway responsiveness to methacholine was not significantly different between control and ovalbumin-challenged animals and was not augmented by OX-8 pretreatment. CD8+ T cells modulate the extent of allergen-induced airway inflammation. However, the enhancement of inflammation was not sufficient to affect airway responsiveness.
Journal of Allergy and Clinical Immunology, 2007
Background: CD8 T cells are known to respond to exogenous antigens through cross-presentation. The importance of the CD8 cell response in the lung after inhalation of allergen and its effects on asthmatic inflammation are less clear. Objective: We sought to determine the dynamics, nature, and immunoregulatory activities of the class I CD8 T-cell response to inhaled allergen. Methods: We studied a murine model of respiratory allergen sensitization, adoptive transfer of transgenic T cells, and flow cytometric analysis of lung infiltrates. Results: Class I-restricted CD8 T cells responded rapidly to inhaled allergen and dominated the acute infiltration of T cells into the lung after secondary exposure. CD8 cells in the lung expressed a type 1 phenotype and suppressed the systemic IgE response to subsequent immunization. Dendritic cells purified from conducting airways or lung tissue were highly efficient at cross-presentation of antigen into the class I pathway after intranasal challenge. Adoptive transfer of transgenic antigenspecific CD8, but not CD4, cells resulted in increased IL-12 levels and reduced IL-13 and IL-5 levels in bronchoalveolar lavage fluid, coupled with substantially reduced airway eosinophilia after repeated allergen inhalation, a process mimicked by intranasal administration of IL-12 and inhibited by anti-IL-12 antibody. Conclusion: The data suggest that CD8 cells specific for inhaled allergens are generated in draining lymph nodes but suppress allergic airway inflammation through induction of IL-12 in the lung during interaction with respiratory dendritic cells. Clinical implications: Novel peptide immunotherapeutics targeting the class I-restricted CD8 T-cell response to allergen represent a promising strategy for extrinsic asthma. (J Allergy Clin Immunol 2007;119:226-34.)
The effects of CD8+γδ T cells on late allergic airway responses and airway inflammation in rats
Journal of Allergy and Clinical Immunology, 2003
Background: Gamma-delta (γδ) T cells regulate immune responses to foreign protein at mucosal surfaces. Whether they can modify allergen-induced early (EAR) and late airway responses (LAR) is unknown. Objective: We have tested the hypothesis that the CD8 + subtype of γδ T cells decreases allergen-induced LAR and airway eosinophilia in the rat. Methods: Brown Norway rats were administered, intraperitoneally, 3.5 × 10 4 lymph node CD8 + γδ T cells from naive or sensitized rats. The recipients were sensitized to ovalbumin (OVA) in Al(OH) 3 3 days after cell transfer and challenged with aerosolized OVA 14 days later. Serum IgE was measured before allergen challenge. After challenge, lung resistance was monitored for 8 hours and then bronchoalveolar lavage (BAL) was analyzed for eosinophil major basic protein (MBP), IL-4, IL-5, IL-13, and IFN-γ messenger RNA-expressing cells. Results: γδ T cells from naive donors significantly decreased LAR in OVA-challenged sensitized rats, whereas MBP + eosinophils were decreased by both γδ T cells from naive and sensitized donors. EAR and serum IgE levels were unchanged. The expression of IL-4, IL-5, and IL-13 by BAL cells of γδ T cell recipients was attenuated compared with OVA-challenged controls. This was accompanied by an increase in the expression of IFN-γ. Conclusions: Our results are consistent with a suppressive role of CD8 + γδ T cells on allergic airway responses. However, only γδ T cells from naive donors inhibit LAR.
CD8+ T Cells Modulate Late Allergic Airway Responses in Brown Norway Rats
The Journal of Immunology
To test the hypothesis that CD8+ T cells may suppress the allergen-induced late airway response (LAR) and airway eosinophilia, we examined the effect of administration of Ag-primed CD8+ T cells on allergic airway responses, bronchoalveolar lavage (BAL) leukocytes, and mRNA expression for cytokines (IL-4, IL-5, and IFN-γ) in OVA-sensitized Brown Norway rats. On day 12 postsensitization to OVA, test rats were administered 2 million CD8+ T cells i.p. isolated from either the cervical lymph nodes (LN group; n = 8) or the spleen (Spl group; n = 6) of sensitized donors. On day 14, test rats were challenged with aerosolized OVA. Control rats were administered PBS i.p. on day 12, and challenged with OVA (n = 10) or BSA (n = 6) on day 14. The lung resistance was measured for 8 h after challenge. BAL was performed at 8 h. Cytospin slides of BAL were analyzed for major basic protein by immunostaining and for cytokine mRNA by in situ hybridization. The LAR was significantly less in the LN group...
Journal of Allergy and Clinical Immunology, 2002
Background: CD8 + T cells can suppress allergen-induced late airway responses (LARs) and airway inflammation. Objective: To test the hypothesis that the suppression of LARs and airway eosinophilia by CD8 + T cells is IFN-γ mediated, we tested the effects of adoptively transferred CD8 + T cells, in which IFN-γ synthesis was inhibited by an antisense (AS) oligodeoxynucleotide (ODN), on the airway responses of a rat model of allergic asthma. Methods: CD8 + T cells were harvested from the cervical lymph nodes of ovalbumin (OVA)-sensitized Brown Norway rats for administration to other actively sensitized syngeneic rats. CD8 + T cells (2 × 10 6) were incubated for 6 hours with 2 µmol/L AS ODN or sense ODN and were injected intraperitoneally into recipients; inhibition of IFN-γ expression in vitro by AS ODN was shown by means of flow cytometry. Two days later, rats were challenged with aerosolized OVA. Results: OVA-induced LAR and bronchoalveolar lavage (BAL) fluid eosinophilia were suppressed by sense ODN-treated CD8 + T cells. IFN-γ expression in BAL cells was elevated in these animals. IFN-γ expression in BAL cells was at control levels in recipients of AS ODN-treated CD8 + cells, confirming the success of the AS treatment in vivo. BAL eosinophilia was also largely restored in the AS ODN treatment group. In contrast, the CD8 + T cell-induced suppression of the LAR was not significantly affected by AS ODN pretreatment. Conclusions: These results indicate that CD8 + T cells inhibit airway eosinophilia through secretion of IFN-γ but may suppress the LAR by means of other mechanisms. (J Allergy Clin Immunol 2002;109:803-9.)