Fatty acid amide hydrolase shapes NKT cell responses by influencing the serum transport of lipid antigen in mice
| Autor: | Joanna Pawlak, Benjamin F. Cravatt, Kim Masuda, Stefan Freigang, Yang Liu, Victoria Zadorozhny, Lisa Kain, Rana Herro, Nicolas Schrantz, Philippe Krebs, Paul B. Savage, Luc Teyton, Michele K. McKinney, Albert Bendelac |
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| Rok vydání: | 2010 |
| Předmět: |
T-Lymphocytes
medicine.medical_treatment Cell Galactosylceramides chemical and pharmacologic phenomena Lymphocyte Activation Amidohydrolases Mice 03 medical and health sciences 0302 clinical medicine Immune system Adjuvants Immunologic Antigen Fatty acid amide hydrolase medicine Animals Antigens 030304 developmental biology 0303 health sciences biology hemic and immune systems General Medicine Natural killer T cell 3. Good health Cell biology Mice Inbred C57BL CTL medicine.anatomical_structure Cytokine CD1D Immunology biology.protein Natural Killer T-Cells lipids (amino acids peptides and proteins) Glycolipids T-Lymphocytes Cytotoxic Research Article 030215 immunology |
| Zdroj: | Journal of Clinical Investigation The Journal of clinical investigation |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci40451 |
| Popis: | 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 alpha-galactosylceramide (alphaGalCer) is the proto-typic 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 alphaGalCer-binding protein that modulates the induction of key effector functions of NKT cells in vivo. FAAH bound alphaGalCer in vivo and in vitro and was required for the efficient targeting of lipid antigens for CD1d presentation. Immunization of Faah-deficient mice with alphaGalCer 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. |
| Databáze: | OpenAIRE |
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