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OX40 (CD134) controls memory T helper 2 cells that drive lung inflammation.

Salek-Ardakani S, Song J, Halteman BS, Jember AG, Akiba H, Yagita H, Croft M - J. Exp. Med. (2003)

Bottom Line: In already sensitized animals, blocking OX40-OX40L interactions at the time of inhalation of aerosolized antigen suppressed memory effector accumulation in lung draining lymph nodes and lung, and prevented eosinophilia, airway hyperreactivity, mucus secretion, and Th2 cyto-kine production.Demonstrating that OX40 signals directly regulate memory T cells, antigen-experienced OX40-deficient T cells were found to divide initially but could not survive and accumulate in large numbers after antigen rechallenge.Thus, OX40-OX40L interactions are pivotal to the efficiency of recall responses regulated by memory Th2 cells.

View Article: PubMed Central - PubMed

Affiliation: La Jolla Institute for Allergy and Immunology, Division of Immunochemistry, 10355 Science Center Dr., San Diego, CA 92121, USA.

ABSTRACT
Asthma is caused by memory Th2 cells that often arise early in life and persist after repeated encounters with allergen. Although much is known regarding how Th2 cells develop, there is little information about the molecules that regulate memory Th2 cells after they have formed. Here we show that the costimulatory molecule OX40 is expressed on memory CD4 cells. In already sensitized animals, blocking OX40-OX40L interactions at the time of inhalation of aerosolized antigen suppressed memory effector accumulation in lung draining lymph nodes and lung, and prevented eosinophilia, airway hyperreactivity, mucus secretion, and Th2 cyto-kine production. Demonstrating that OX40 signals directly regulate memory T cells, antigen-experienced OX40-deficient T cells were found to divide initially but could not survive and accumulate in large numbers after antigen rechallenge. Thus, OX40-OX40L interactions are pivotal to the efficiency of recall responses regulated by memory Th2 cells.

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Anti-OX40L inhibits lung infiltration, goblet cell hyperplasia, mucus, serum IgE, and BAL Th2 cytokine production. Groups of mice were immunized and challenged as described in Fig. 2. 24 h after the final OVA aerosol challenge, lung tissue was stained with H&E (×100) for quantitation of inflammatory infiltrates (A and B) and periodic acid-Schiff (PAS, ×200; purple-red staining) to highlight the mucus-secreting cells (D and E), in sensitized and challenged animals receiving control Ig (A and D) or anti-OX40L (B and E). Sections were graded for inflammation severity (C) and mucus production (F) with groups A (white bars), B (black bars), and C (gray bars) corresponding to those described in Fig. 2. Results are the mean score ± SEM from four separate experiments with four mice per group in each experiment. 24 h after the final OVA aerosol challenge, sera were analyzed for OVA-specific IgE (G), and BAL were assessed for IL-4 (H), IL-5 (I), IL-9 (J), and IL-13 (K). Results are the mean values ± SEM from two separate experiments with four mice per group in each experiment.
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fig3: Anti-OX40L inhibits lung infiltration, goblet cell hyperplasia, mucus, serum IgE, and BAL Th2 cytokine production. Groups of mice were immunized and challenged as described in Fig. 2. 24 h after the final OVA aerosol challenge, lung tissue was stained with H&E (×100) for quantitation of inflammatory infiltrates (A and B) and periodic acid-Schiff (PAS, ×200; purple-red staining) to highlight the mucus-secreting cells (D and E), in sensitized and challenged animals receiving control Ig (A and D) or anti-OX40L (B and E). Sections were graded for inflammation severity (C) and mucus production (F) with groups A (white bars), B (black bars), and C (gray bars) corresponding to those described in Fig. 2. Results are the mean score ± SEM from four separate experiments with four mice per group in each experiment. 24 h after the final OVA aerosol challenge, sera were analyzed for OVA-specific IgE (G), and BAL were assessed for IL-4 (H), IL-5 (I), IL-9 (J), and IL-13 (K). Results are the mean values ± SEM from two separate experiments with four mice per group in each experiment.

Mentions: To support the findings from lung lavages we conducted histological evaluations on lung sections. Mice receiving control Ab developed inflammatory lesions, characterized by a predominance of eosinophils and lymphocytes (Fig. 3, A and C) , together with hyperplasia of the mucus-secreting bronchial epithelial cells (Fig. 3 A). In contrast, lungs from anti-OX40L treated animals had almost normal bronchial epithelium, and a minimum of infiltrating cells around the bronchioles and blood vessels (Fig. 3, B and C). Many PAS+ (mucus-secreting) cells were detected in the airway of mice that were sensitized and challenged and received the control Ab (Fig. 3, D and F), whereas treatment with anti-OX40L markedly reduced the number of PAS+ cells (Fig. 3, E and F).


OX40 (CD134) controls memory T helper 2 cells that drive lung inflammation.

Salek-Ardakani S, Song J, Halteman BS, Jember AG, Akiba H, Yagita H, Croft M - J. Exp. Med. (2003)

Anti-OX40L inhibits lung infiltration, goblet cell hyperplasia, mucus, serum IgE, and BAL Th2 cytokine production. Groups of mice were immunized and challenged as described in Fig. 2. 24 h after the final OVA aerosol challenge, lung tissue was stained with H&E (×100) for quantitation of inflammatory infiltrates (A and B) and periodic acid-Schiff (PAS, ×200; purple-red staining) to highlight the mucus-secreting cells (D and E), in sensitized and challenged animals receiving control Ig (A and D) or anti-OX40L (B and E). Sections were graded for inflammation severity (C) and mucus production (F) with groups A (white bars), B (black bars), and C (gray bars) corresponding to those described in Fig. 2. Results are the mean score ± SEM from four separate experiments with four mice per group in each experiment. 24 h after the final OVA aerosol challenge, sera were analyzed for OVA-specific IgE (G), and BAL were assessed for IL-4 (H), IL-5 (I), IL-9 (J), and IL-13 (K). Results are the mean values ± SEM from two separate experiments with four mice per group in each experiment.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2194076&req=5

fig3: Anti-OX40L inhibits lung infiltration, goblet cell hyperplasia, mucus, serum IgE, and BAL Th2 cytokine production. Groups of mice were immunized and challenged as described in Fig. 2. 24 h after the final OVA aerosol challenge, lung tissue was stained with H&E (×100) for quantitation of inflammatory infiltrates (A and B) and periodic acid-Schiff (PAS, ×200; purple-red staining) to highlight the mucus-secreting cells (D and E), in sensitized and challenged animals receiving control Ig (A and D) or anti-OX40L (B and E). Sections were graded for inflammation severity (C) and mucus production (F) with groups A (white bars), B (black bars), and C (gray bars) corresponding to those described in Fig. 2. Results are the mean score ± SEM from four separate experiments with four mice per group in each experiment. 24 h after the final OVA aerosol challenge, sera were analyzed for OVA-specific IgE (G), and BAL were assessed for IL-4 (H), IL-5 (I), IL-9 (J), and IL-13 (K). Results are the mean values ± SEM from two separate experiments with four mice per group in each experiment.
Mentions: To support the findings from lung lavages we conducted histological evaluations on lung sections. Mice receiving control Ab developed inflammatory lesions, characterized by a predominance of eosinophils and lymphocytes (Fig. 3, A and C) , together with hyperplasia of the mucus-secreting bronchial epithelial cells (Fig. 3 A). In contrast, lungs from anti-OX40L treated animals had almost normal bronchial epithelium, and a minimum of infiltrating cells around the bronchioles and blood vessels (Fig. 3, B and C). Many PAS+ (mucus-secreting) cells were detected in the airway of mice that were sensitized and challenged and received the control Ab (Fig. 3, D and F), whereas treatment with anti-OX40L markedly reduced the number of PAS+ cells (Fig. 3, E and F).

Bottom Line: In already sensitized animals, blocking OX40-OX40L interactions at the time of inhalation of aerosolized antigen suppressed memory effector accumulation in lung draining lymph nodes and lung, and prevented eosinophilia, airway hyperreactivity, mucus secretion, and Th2 cyto-kine production.Demonstrating that OX40 signals directly regulate memory T cells, antigen-experienced OX40-deficient T cells were found to divide initially but could not survive and accumulate in large numbers after antigen rechallenge.Thus, OX40-OX40L interactions are pivotal to the efficiency of recall responses regulated by memory Th2 cells.

View Article: PubMed Central - PubMed

Affiliation: La Jolla Institute for Allergy and Immunology, Division of Immunochemistry, 10355 Science Center Dr., San Diego, CA 92121, USA.

ABSTRACT
Asthma is caused by memory Th2 cells that often arise early in life and persist after repeated encounters with allergen. Although much is known regarding how Th2 cells develop, there is little information about the molecules that regulate memory Th2 cells after they have formed. Here we show that the costimulatory molecule OX40 is expressed on memory CD4 cells. In already sensitized animals, blocking OX40-OX40L interactions at the time of inhalation of aerosolized antigen suppressed memory effector accumulation in lung draining lymph nodes and lung, and prevented eosinophilia, airway hyperreactivity, mucus secretion, and Th2 cyto-kine production. Demonstrating that OX40 signals directly regulate memory T cells, antigen-experienced OX40-deficient T cells were found to divide initially but could not survive and accumulate in large numbers after antigen rechallenge. Thus, OX40-OX40L interactions are pivotal to the efficiency of recall responses regulated by memory Th2 cells.

Show MeSH
Related in: MedlinePlus