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Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen.

Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K - J. Exp. Med. (2002)

Bottom Line: Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming.The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells.In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.

ABSTRACT
Allergic asthma is an inflammatory lung disease initiated and directed by T helper cells type 2 (Th2). The mechanism involved in generation of Th2 responses to inert inhaled antigens, however, is unknown. Epidemiological evidence suggests that exposure to lipopolysaccharide (LPS) or other microbial products can influence the development and severity of asthma. However, the mechanism by which LPS influences asthma pathogenesis remains undefined. Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming. Here, we report that low level inhaled LPS signaling through TLR4 is necessary to induce Th2 responses to inhaled antigens in a mouse model of allergic sensitization. The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells. In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses. These studies suggest that the level of LPS exposure can determine the type of inflammatory response generated and provide a potential mechanistic explanation of epidemiological data on endotoxin exposure and asthma prevalence.

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Th2 pulmonary responses and DC activation in response to OVA with LPS are abrogated in TLR4d mice but can be restored with TNF-α. (A) We sensitized mice as before with half of groups receiving 2 μg recombinant murine TNF-α (R&D Systems) intranasally on day 1. The number of inflammatory cells recovered by BAL on day 21 is represented by the height of the stacked bars with error bars. *, P < 0.001 (WT vs. TLR4d); **, P = 0.001 (TLR4d vs. TLR4d with TNF-α). (B) MHC II and B7.2 FACS® analysis of CDllchi BMDCs from WT or TLR4d stimulated for 12 h with PBS, 100 μg/ml OVA/LPS, or 100 ng/ml TNF-α. (C) Number of FITC+ CDllc+ cells in mediastinal LNs on day 3 after intranasal administration of FITC-OVA with low dose (0.1 μg) LPS (gray bars) with (+) or without (−) 2 μg intranasal TNF-α (solid bars) on day 1. One representative experiment of three is shown. *, P = 0.01 (TLR4d + vs. − TNF-α).
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fig4: Th2 pulmonary responses and DC activation in response to OVA with LPS are abrogated in TLR4d mice but can be restored with TNF-α. (A) We sensitized mice as before with half of groups receiving 2 μg recombinant murine TNF-α (R&D Systems) intranasally on day 1. The number of inflammatory cells recovered by BAL on day 21 is represented by the height of the stacked bars with error bars. *, P < 0.001 (WT vs. TLR4d); **, P = 0.001 (TLR4d vs. TLR4d with TNF-α). (B) MHC II and B7.2 FACS® analysis of CDllchi BMDCs from WT or TLR4d stimulated for 12 h with PBS, 100 μg/ml OVA/LPS, or 100 ng/ml TNF-α. (C) Number of FITC+ CDllc+ cells in mediastinal LNs on day 3 after intranasal administration of FITC-OVA with low dose (0.1 μg) LPS (gray bars) with (+) or without (−) 2 μg intranasal TNF-α (solid bars) on day 1. One representative experiment of three is shown. *, P = 0.01 (TLR4d + vs. − TNF-α).

Mentions: Adjuvants initiate adaptive immune responses by activating DCs to present antigen in the context of MHC and costimulatory molecules in the DLN (3). We hypothesized that if we could induce DC maturation and migration in the absence of LPS adjuvant signals in TLR4d mice, we could restore T cell priming to inhaled antigen. TNF-α is both a product of LPS-stimulated DCs and is known to activate DCs. Using this cytokine to circumvent deficient maturation signals by LPS, Th2 responses were completely restored in TLR4d mice with administered TNF-α during sensitization to inhaled antigen. This included airway inflammatory responses (Fig. 4 A) and antibody responses (not depicted). In addition, TNF-α administration restored DLN cytokine production in TLR4d mice (116 ± 22 vs. 1516 ± 590 pg/ml IL-5 and 524 ± 130 vs. 2225 ± 1186 pg/ml IL-13 in TLR4d vs. TLR4d with TNF-α, respectively). These data indicate that defective T cell priming can be overcome using the LPS/TLR-induced cytokine TNF-α, implicating a role for DC maturation and migration in the LPS adjuvant effect.


Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen.

Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K - J. Exp. Med. (2002)

Th2 pulmonary responses and DC activation in response to OVA with LPS are abrogated in TLR4d mice but can be restored with TNF-α. (A) We sensitized mice as before with half of groups receiving 2 μg recombinant murine TNF-α (R&D Systems) intranasally on day 1. The number of inflammatory cells recovered by BAL on day 21 is represented by the height of the stacked bars with error bars. *, P < 0.001 (WT vs. TLR4d); **, P = 0.001 (TLR4d vs. TLR4d with TNF-α). (B) MHC II and B7.2 FACS® analysis of CDllchi BMDCs from WT or TLR4d stimulated for 12 h with PBS, 100 μg/ml OVA/LPS, or 100 ng/ml TNF-α. (C) Number of FITC+ CDllc+ cells in mediastinal LNs on day 3 after intranasal administration of FITC-OVA with low dose (0.1 μg) LPS (gray bars) with (+) or without (−) 2 μg intranasal TNF-α (solid bars) on day 1. One representative experiment of three is shown. *, P = 0.01 (TLR4d + vs. − TNF-α).
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Related In: Results  -  Collection

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fig4: Th2 pulmonary responses and DC activation in response to OVA with LPS are abrogated in TLR4d mice but can be restored with TNF-α. (A) We sensitized mice as before with half of groups receiving 2 μg recombinant murine TNF-α (R&D Systems) intranasally on day 1. The number of inflammatory cells recovered by BAL on day 21 is represented by the height of the stacked bars with error bars. *, P < 0.001 (WT vs. TLR4d); **, P = 0.001 (TLR4d vs. TLR4d with TNF-α). (B) MHC II and B7.2 FACS® analysis of CDllchi BMDCs from WT or TLR4d stimulated for 12 h with PBS, 100 μg/ml OVA/LPS, or 100 ng/ml TNF-α. (C) Number of FITC+ CDllc+ cells in mediastinal LNs on day 3 after intranasal administration of FITC-OVA with low dose (0.1 μg) LPS (gray bars) with (+) or without (−) 2 μg intranasal TNF-α (solid bars) on day 1. One representative experiment of three is shown. *, P = 0.01 (TLR4d + vs. − TNF-α).
Mentions: Adjuvants initiate adaptive immune responses by activating DCs to present antigen in the context of MHC and costimulatory molecules in the DLN (3). We hypothesized that if we could induce DC maturation and migration in the absence of LPS adjuvant signals in TLR4d mice, we could restore T cell priming to inhaled antigen. TNF-α is both a product of LPS-stimulated DCs and is known to activate DCs. Using this cytokine to circumvent deficient maturation signals by LPS, Th2 responses were completely restored in TLR4d mice with administered TNF-α during sensitization to inhaled antigen. This included airway inflammatory responses (Fig. 4 A) and antibody responses (not depicted). In addition, TNF-α administration restored DLN cytokine production in TLR4d mice (116 ± 22 vs. 1516 ± 590 pg/ml IL-5 and 524 ± 130 vs. 2225 ± 1186 pg/ml IL-13 in TLR4d vs. TLR4d with TNF-α, respectively). These data indicate that defective T cell priming can be overcome using the LPS/TLR-induced cytokine TNF-α, implicating a role for DC maturation and migration in the LPS adjuvant effect.

Bottom Line: Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming.The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells.In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.

ABSTRACT
Allergic asthma is an inflammatory lung disease initiated and directed by T helper cells type 2 (Th2). The mechanism involved in generation of Th2 responses to inert inhaled antigens, however, is unknown. Epidemiological evidence suggests that exposure to lipopolysaccharide (LPS) or other microbial products can influence the development and severity of asthma. However, the mechanism by which LPS influences asthma pathogenesis remains undefined. Although it is known that signaling through Toll-like receptors (TLR) is required for adaptive T helper cell type 1 (Th1) responses, it is unclear if TLRs are needed for Th2 priming. Here, we report that low level inhaled LPS signaling through TLR4 is necessary to induce Th2 responses to inhaled antigens in a mouse model of allergic sensitization. The mechanism by which LPS signaling results in Th2 sensitization involves the activation of antigen-containing dendritic cells. In contrast to low levels, inhalation of high levels of LPS with antigen results in Th1 responses. These studies suggest that the level of LPS exposure can determine the type of inflammatory response generated and provide a potential mechanistic explanation of epidemiological data on endotoxin exposure and asthma prevalence.

Show MeSH
Related in: MedlinePlus