Leukotriene B4 Receptor-1 Is Essential for Allergen-Mediated Recruitment of CD8+ T Cells and Airway Hyperresponsiveness

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Dendritic cells (DC) are important APCs that control allergen-induced airway responses by interacting directly with T cells. Leukotriene B4 (LTB4), interacting with its high-affinity receptor, LTB4 receptor 1 (BLT1), is known to attract and activate leukocytes during inflammation. We have previously shown that BLT1 expression on Ag-primed T cells is required for the development of airway hyperresponsiveness (AHR; Miyahara et al. 2005. Am. J. Respir. Crit. Care Med. 172: 161–167). However, the role for the LTB4-BLT1 pathway in DC function in allergen-induced airway responses has not been defined. Bone marrow-derived DCs (BMDC) were generated. Naive BALB/c mice received OVA-pulsed BLT1-deficient (BLT1−/−) BMDCs or wild-type BMDCs intratracheally and were then challenged with OVA for 3 days. Airway responses were monitored 48 h after the last allergen challenge. BLT1−/− BMDCs showed normal maturation judged from surface expression of CD markers. Compared with recipients of wild-type BMDCs, mice that received BLT1−/− BMDCs developed significantly lower AHR to inhaled methacholine, lower goblet cell metaplasia, and eosinophilic infiltration in the airways and decreased levels of Th2 type cytokines in the bronchoalveolar lavage fluid. Migration of BLT1−/− BMDCs into peribronchial lymph nodes was significantly impaired compared with BLT1+/+ BMDCs after intratracheal instillation. These data suggest that BLT1 expression on DCs is required for migration of DCs to regional lymph nodes as well as in the development of AHR and airway inflammation.

Section: Discussionsupporting

confidence: 80%

Leukotriene B4 Receptor 1 Expression on Dendritic Cells Is Required for the Development of Th2 Responses and Allergen-Induced Airway Hyperresponsiveness

Miyahara

Ohnishi

Matsuda

et al. 2008

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“…ϩ BLT1 ϩ/ϩ T cells from OT-I mice fully restored the reduced AHR, airway eosinophilia, and IL-13 production in CD8-null mice (50). Thus, LTB 4 -BLT1 interaction plays an important role in initiating and developing Th2-type immune response by attracting CD8 ϩ effector T cells into the lung to produce IL-13, and stimulating T cells to produce IL-4 and -5 in the LN, providing a novel idea about how LTB 4 plays immunological roles.…”

Section: Discussionmentioning

confidence: 99%

Absence of Leukotriene B4 Receptor 1 Confers Resistance to Airway Hyperresponsiveness and Th2-Type Immune Responses

Terawaki

Yokomizo²,

Nagase³

et al. 2005

155

147

Bronchial asthma is an increasingly common disorder that remains poorly understood and difficult to manage. The disease is characterized by airway hyperresponsiveness, chronic inflammation, and mucus overproduction. Based on the finding that leukotriene B4 receptor 1 (BLT1) is expressed highly in Th2 lymphocytes, we analyzed the roles of BLT1 using an OVA-induced bronchial asthma model. BLT1-null mice did not develop airway hyperresponsiveness, eosinophilic inflammation, and hyperplasia of goblet cells. Attenuated symptoms were accompanied by reduced IgE production, and accumulation of IL-5 and IL-13 in bronchoalveolar lavage fluid, suggesting attenuated Th2-type immune response in BLT1-null mice. Peribronchial lymph node cells of sensitized BLT1-null mice showed much attenuated proliferation and production of Th2 cytokines upon re-stimulation with Ag in vitro. Thus, LTB4-BLT1 axis is required for the development of Th2-type immune response, and blockade of LTB4 functions through BLT1 would be novel and useful in the effort to ameliorate bronchial asthma and related Th2-biased immune disorders.

“…Mice lacking expression of the high-affinity receptor for LTB4 (BLT1) failed to develop AHR following systemic sensitization and challenge (29). BLT1 Ϫ/Ϫ mice similarly showed no increase in airway reactivity following passive sensitization and OVA exposure when compared with WT mice (Fig.…”

Section: Development Of Increased Airway Reactivity Following Passivementioning

confidence: 99%

“…We have shown that BLT1 expression on T EFF is essential for development of AHR following systemic sensitization and challenge (29) and that BLT1 Ϫ/Ϫ mice fail to develop altered airway reactivity following passive sensitization and challenge. Cumulatively, these data indicated that CD8 ϩ T EFF were essential to the development of altered airway responsiveness following passive sensitization and airway challenge and that their function is dependent on the expression of BLT1, BLT1 mediating their accumulation in the lung.…”

Section: Increased Airway Reactivity Following T Eff Can Be Abolishedmentioning

confidence: 99%

The Leukotriene B4 Receptor (BLT1) Is Required for Effector CD8+ T Cell-Mediated, Mast Cell-Dependent Airway Hyperresponsiveness

Taube

Miyahara

Ott

et al. 2006

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Studies in both humans and rodents have suggested that CD8+ T cells contribute to the development of airway hyperresponsiveness (AHR) and that leukotriene B4 (LTB4) is involved in the chemotaxis of effector CD8+ T cells (TEFF) to the lung by virtue of their expression of BLT1, the receptor for LTB4. In the present study, we used a mast cell-CD8-dependent model of AHR to further define the role of BLT1 in CD8+ T cell-mediated AHR. C57BL/6+/+ and CD8-deficient (CD8−/−) mice were passively sensitized with anti-OVA IgE and exposed to OVA via the airways. Following passive sensitization and allergen exposure, C57BL/6+/+ mice developed altered airway function, whereas passively sensitized and allergen-exposed CD8−/− mice failed to do so. CD8−/− mice reconstituted with CD8+ TEFF developed AHR in response to challenge. In contrast, CD8−/− mice reconstituted with BLT1-deficient effector CD8+ T cells did not develop AHR. The induction of increased airway responsiveness following transfer of CD8+ TEFF or in wild-type mice could be blocked by administration of an LTB4 receptor antagonist confirming the role of BLT1 in CD8+ T cell-mediated AHR. Together, these data define the important role for mast cells and the LTB4-BLT1 pathway in the development of CD8+ T cell-mediated allergic responses in the lung.