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Antagonism of Airway Tolerance by Endotoxin/Lipopolysaccharide through Promoting OX40L and Suppressing Antigen-Specific Foxp3⁺ T Regulatory Cells¹

Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037

Respiratory exposure to allergens can lead to airway tolerance. Factors that antagonize tolerance mechanisms in the lung might result in susceptibility to diseases such as asthma. We show that inhalation of endotoxin/LPS with Ag prevented airway tolerance and abolished protection from T cell-driven asthmatic lung inflammation. Under conditions leading to tolerance, adaptive Ag-specific CD4⁺Foxp3⁺ T regulatory cells (Treg) were generated following exposure to intranasal Ag and outnumbered IL-4- and IFN--producing CD4 T cells by 100:1 or greater. Inhaled LPS altered the ratio of Treg to IL-4⁺ or IFN-⁺ T cells by concomitantly suppressing Treg generation and promoting effector T cell generation. LPS induced OX40L expression on dendritic cells and B cells that resulted in a synergistic activity between TLR4 and OX40 signals, leading to production of IL-4, IFN-, and IL-6, which blocked Treg development. Furthermore, inhibiting OX40/OX40L interactions prevented LPS from suppressing tolerance, and resulted in the generation of greater numbers of adaptive Treg. Thus, cooperation between TLR4 and OX40 controls susceptibility to developing airway disease via modulating the balance between adaptive Treg and IL-4⁺ or IFN-⁺ T cells. Targeting OX40L then has the potential to improve the efficacy of Ag immunotherapy to promote tolerance.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI070535 and CA91837 (to M.C.). This is manuscript 1032 from the La Jolla Institute for Allergy and Immunology.

² Address correspondence and reprint requests to Dr. Michael Croft, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: mick{at}liai.org

³ Abbreviations used in this paper: Treg, regulatory T cell; BAL, bronchoalveolar lavage; i.n., intranasal; KO, knockout; MCC, moth cytochrome c; wt, wild type.