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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Sibilano, Riccardo Frossi, Barbara Suzuki, Ryo D'Incà, Federica Gri, Giorgia Piconese, Silvia Colombo, Mario P. Rivera, Juan Pucillo, Carlo E. |
| Description | Country affiliation: Italy Author Affiliation: Sibilano R ( Department of Medical and Biological Sciences, University of Udine, Udine, Italy.) |
| Abstract | BACKGROUND: The interaction of mast cells (MCs) with regulatory T cells through the OX40 ligand (OX40L):OX40 axis downregulates FcεRI-dependent immediate hypersensitivity responses both in vitro and in vivo. Little is known on OX40L-mediated intracellular signaling or on the mechanism by which OX40L engagement suppresses MC degranulation. OBJECTIVE: We explored the role of OX40L engagement on IgE/antigen-triggered MCs both in vitro and in vivo. METHODS: The soluble form of OX40 molecule was used to selectively trigger OX40L on MCs in vitro and was used to dissect OX40L contribution in an in vivo model of systemic anaphylaxis. RESULTS: OX40L:OX40 interaction led to the recruitment of C-terminal src kinase into lipid rafts, causing a preferential suppression of Fyn kinase activity and subsequent reduction in the phosphorylation of Gab2, the phosphatidylinositol 3-OH kinase regulatory subunit p85, and Akt, without affecting the Lyn pathway. Dampening of Fyn kinase activity also inhibited RhoA activation and microtubule nucleation, key regulators of MC degranulation. The in vivo administration of a blocking antibody to OX40L in wild-type mice caused enhanced immediate hypersensitivity, whereas the administration of soluble OX40 to regulatory T-cell-depleted or OX40-deficient mice reduced MC degranulation. CONCLUSIONS: The engagement of OX40L selectively suppresses Fyn-initiated signals required for MC degranulation and serves to limit immediate hypersensitivity. Our data suggest that soluble OX40 can restore the aberrant or absent regulatory T-cell activity, revealing a previously unappreciated homeostatic role for OX40L in setting the basal threshold of MC response. |
| File Format | HTM / HTML |
| ISSN | 00916749 |
| e-ISSN | 10976825 |
| Journal | Journal of Allergy and Clinical Immunology |
| Issue Number | 3 |
| Volume Number | 130 |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2012-09-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Discipline Immunology Mast Cells Physiology Membrane Glycoproteins Phosphatidylinositol 3-kinases Proto-oncogene Proteins C-fyn Receptors, Ige Tumor Necrosis Factors Rho Gtp-binding Proteins Anaphylaxis Etiology Animals Membrane Microdomains Metabolism Mice Mice, Inbred C57bl Microtubules Phosphoproteins Phosphorylation Research Support, Non-u.s. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Allergy Immunology |
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