Costimulation of mast cells by 4-1BB, a member of the tumor necrosis factor receptor superfamily, with the high-affinity IgE receptor

Mast cells are the major effector-cell type for immediate hypersensitivity and other forms of allergic reactions. Expression of 4-1BB, a member of the tumor necrosis factor receptor superfamily, is induced at mRNA and protein levels on stimulation through the high-affinity receptor for immunoglobulin E (IgE; Fc epsilon RI). In this study, we present evidence that agonistic anti-4-1BB antibodies can enhance Fc epsilon RI-induced cytokine production and secretion. Consistent with this, 4-1 BB-deficient mast cells exhibit reduced degranulation and cytokine production on Fc epsilon RI stimulation. Analysis of 4-1 BB ligand (4-1 BBL)deficient cells supported this notion. As a potential mechanism for these defects, we identified a defect in Ca2+ flux induced by Fc epsilon RI stimulation. The defective Ca2+ flux could be accounted for by the reduced activity of Lyn/Btk/phospholipase C-gamma 2 pathway and constitutive interactions between 4-1BB and Lyn. Therefore, Fc epsilon RI-inducible 4-1BB plays a costimulatory function together with Fc epsilon RI stimulation.