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Corticosteroids enhance CD8+ T cell–mediated airway hyperresponsiveness and allergic inflammation by upregulating leukotriene B4 receptor 1  Hiroshi Ohnishi,

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Presentation on theme: "Corticosteroids enhance CD8+ T cell–mediated airway hyperresponsiveness and allergic inflammation by upregulating leukotriene B4 receptor 1  Hiroshi Ohnishi,"— Presentation transcript:

1 Corticosteroids enhance CD8+ T cell–mediated airway hyperresponsiveness and allergic inflammation by upregulating leukotriene B4 receptor 1  Hiroshi Ohnishi, MD, PhD, Nobuaki Miyahara, MD, PhD, Azzeddine Dakhama, PhD, Katsuyuki Takeda, MD, PhD, Steven Mathis, PhD, Bodduluri Haribabu, PhD, Erwin W. Gelfand, MD  Journal of Allergy and Clinical Immunology  Volume 121, Issue 4, Pages e4 (April 2008) DOI: /j.jaci Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 DEX upregulates BLT1 on CD8+ TEFFs but not TCMs. A, Surface expression of BLT1 on TCMs, DEX-treated TCMs, TEFFs, DEX-treated TEFFs, and BLT1-deficient DEX-treated TEFFs. DEX (100 nM) was added to the culture medium during differentiation of TEFFs, TCMs, or BLT1-deficient TEFFs. Cells were studied after 7 days in culture. Staining of these cells with an isotype control showed similar staining as TCMs. B, Surface expression of BLT1 on TEFFs treated with different doses of DEX ( nM). The data shown are representative of 3 independent experiments. APC, Allophycocyanin; SAV, streptavidin. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 DEX treatment augments LTB4-induced phosphorylation of ERK1/2 but not p38 MAPK or JNK. A, Time course of LTB4-induced phosphorylation of MAPKs in TEFFs. TEFFs after 7 days of culture were stimulated with 100 nmol/L LTB4 for 1, 5, 15, 30, and 60 minutes. Cell lysates were resolved on 10% SDS-PAGE, and the phosphorylated MAPKs were detected by using specific antibodies. B, Dose-dependent activation of ERK1/2 by LTB4 ( nM). Cells were stimulated with LTB4 for 1 minute. C, LTB4-induced phosphorylation of ERK1/2 in TEFFs and DEX-treated TEFFs at day 7 of culture. Data represent results from 3 independent experiments. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Reconstitution of CD8−/− mice with DEX-treated TEFF results in further increases in AHR. Non–DEX-treated TEFFs or DEX-treated TEFFs (5 × 106 cells) were adoptively transferred intravenously into OVA-sensitized recipient CD8−/− mice just before the first airway challenge with aerosolized OVA. AHR was monitored by measuring lung resistance (RL; A) and dynamic compliance (Cdyn; B). ∗P < .05 compared with CD8−/− sensitized and challenged (OVA/OVA) mice. #P < .05 compared with TEFF-transferred CD8−/− OVA/OVA mice. Results for each group are expressed as means ± SEMs (n = 7-8 in each group). C, Cell composition of BAL fluid in OVA-sensitized and OVA-challenged (OVA/OVA) CD8−/− mice after transfer of TEFFs or DEX-treated TEFFs. ∗P < .05 compared with CD8−/− OVA/OVA mice. #P < .05 compared with TEFF-transferred CD8−/− OVA/OVA mice. D, Representative photomicrographs of histologic sections of lung in PBS, TEFF, or DEX-treated TEFF-transferred CD8−/− recipient mice. Original magnification, ×200. HE, Hematoxylin and eosin; PAS, periodic acid–Schiff. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 DEX-induced upregulation of BLT1 expression on TEFFs is mediated through increases in CD122 (IL-2Rβ) and CD25 (IL-2Rα) expression. Surface expression of CD122, CD25, and BLT1 on CD8+ TEFFs, DEX-treated TEFFs, TCMs, and DEX-treated TCMs. Numbers shown in the quadrants indicate percentages of the CD8+ T lymphocyte–gated cell population. The data shown are representative of 3 independent experiments. APC, Allophycocyanin; FITC, fluorescein isothiocyanate; PE, phycoerythrin. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 TEFFs are resistant to DEX
TEFFs are resistant to DEX. A, Susceptibility of CD4+ or CD8+ T-cell subpopulations to DEX. Anti-CD3/anti-CD28–stimulated T cells from spleens and lymph nodes of WT mice were cultured in the presence of DEX (100 nM), IL-2 (20 ng/mL), or both for 7 days. Numbers shown in the quadrants indicate percentages of the total lymphocyte-gated cell population. The data shown are representative of 3 independent experiments. B, Effect of DEX on IL-2– or IL-15–dependent cell growth of CD8+ T cells. SIINFEKL peptide–primed OT-1 CD8+ T cells were cultured in the presence of DEX (100 nM), IL-2 or IL-15 (20 ng/mL), or both. ∗P < .05 compared with IL-15–treated cells. Results for each group are expressed as means ± SEMs (n = 5 in each group). Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 DEX treatment potentiates LTB4-induced intracellular Ca2+ influx in TEFFs but not TCMs. A, LTB4-induced intracellular Ca2+ mobilization in TEFFs. Different doses of LTB4 ( nM) or EtOH were added to indo-1 acetoxymethyl ester–loaded TEFFs at day 7 of culture. B, LTB4 (100 nM)–induced intracellular Ca2+ mobilization in TCMs, DEX-treated TCMs, TEFFs, DEX-treated TEFFs, and BLT1-deficient DEX-treated TEFFs at day 7 of culture. The illustrated experiments are representative of at least 3 performed. Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 DEX treatment augments LTB4-induced chemotaxis in TEFFs
DEX treatment augments LTB4-induced chemotaxis in TEFFs. LTB4-induced chemotaxis in TEFFs, DEX-treated TEFFs, TCMs, DEX-treated TCMs, and BLT1-deficient DEX-treated TEFFs. Cells (5 × 105 cells) at day 7 of culture and LTB4 at different concentrations were added to the upper chamber and lower well, respectively. Chemotactic activity of cells is expressed as the percentage increase in numbers of cells that migrated into the lower chamber after 1 hour's incubation with different doses of LTB4 (0-100 nmol/L). ∗P < .001 compared with TCMs. #P < .005 compared with TEFFs. Results for each group are expressed as means ± SEMs (n = 4 in each group). Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Reconstitution of CD8−/− mice with DEX-treated TEFFs results in further increases in numbers of recruited CD8+ T cells to the BAL fluid and lung. Numbers of CD8+ T cells in the BAL fluid (A) and the right lung (B) in CD8−/− OVA/OVA mice after transfer of TEFFs or DEX-treated TEFFs. ∗P < .05 compared with CD8−/− OVA/OVA mice. #P < .05 compared with TEFF-transferred CD8−/− OVA/OVA mice. Results for each group are expressed as means ± SEMs (n = 7-8 in each group, same mice as shown in Fig 3). Journal of Allergy and Clinical Immunology  , e4DOI: ( /j.jaci ) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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