Fatty acid amide hydrolase shapes NKT cell responses by influencing the serum transport of lipid antigen in mice
Stefan Freigang, … , Benjamin F. Cravatt, Luc Teyton
Stefan Freigang, … , Benjamin F. Cravatt, Luc Teyton
Published May 17, 2010
Citation Information: J Clin Invest. 2010;120(6):1873-1884. https://doi.org/10.1172/JCI40451.
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Research Article Immunology

Fatty acid amide hydrolase shapes NKT cell responses by influencing the serum transport of lipid antigen in mice

Abstract

The potent regulatory properties of NKT cells render this subset of lipid-specific T cells a promising target for immunotherapeutic interventions. The marine sponge glycolipid α-galactosylceramide (αGalCer) is the proto­typic NKT cell agonist, which elicits this function when bound to CD1d. However, our understanding of the in vivo properties of NKT cell agonists and the host factors that control their bioactivity remains very limited. In this report, we isolated the enzyme fatty acid amide hydrolase (FAAH) from mouse serum as an αGalCer-binding protein that modulates the induction of key effector functions of NKT cells in vivo. FAAH bound αGalCer in vivo and in vitro and was required for the efficient targeting of lipid antigens for CD1d presentation. Immunization of Faah-deficient mice with αGalCer resulted in a reduced systemic cytokine production, but enhanced expansion of splenic NKT cells. This distinct NKT response conferred a drastically increased adjuvant effect and strongly promoted protective CTL responses. Thus, our findings identify not only the presence of FAAH in normal mouse serum, but also its critical role in the tuning of immune responses to lipid antigens by orchestrating their transport and targeting for NKT cell activation. Our results suggest that the serum transport of lipid antigens directly shapes the quality of NKT cell responses, which could potentially be modulated in support of novel vaccination strategies.

Authors

Stefan Freigang, Victoria Zadorozhny, Michele K. McKinney, Philippe Krebs, Rana Herro, Joanna Pawlak, Lisa Kain, Nicolas Schrantz, Kim Masuda, Yang Liu, Paul B. Savage, Albert Bendelac, Benjamin F. Cravatt, Luc Teyton

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Figure 2

Aberrant NKT cell activation in Faah-deficient mice.

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Aberrant NKT cell activation in Faah-deficient mice. (A and B) NKT c...
(A and B) NKT cell populations in thymus, spleen, and liver of naive WT and Faah KO mice. Data of individual mice is shown in A and means ± SD of groups of 3 mice from 1 of 3 similar experiments in B. (C) CD1d expression on thymocytes (top panel) and splenocytes (bottom panel) of Faah KO (white histogram) and WT (gray histogram) mice as determined by flow cytometry. (D) Decreased induction of IFN-producing NKT cells in livers and spleens of Faah KO mice 1 hour after injection of 1 μg αGalCer. (E and F) Serum cytokine levels (E) and expansion of NKT cells (F) in blood of Faah KO and WT mice in response to αGalCer injection. (G and H) NKT cell expansion in thymus, liver, and spleen (G), and splenic weight and cell numbers (H) of αGalCer-immunized Faah KO and WT mice at day 3 after immunization with αGalCer. (I) Decreased systemic cytokine production and enhanced NKT cell expansion depends on FAAH protein but is independent of CB signaling. WT mice were pretreated with FAAH inhibitor JP104, CB1/2 receptor mimetic WIN 55212-2, or vehicle before i.v. immunization with αGalCer. Data (mean ± SEM) are representative of 2 experiments with 3 mice per group (D, E, and I) or 4 mice per group (F), and of 3 experiments with 3 mice per group (G and H).