SHIP Represses Th2 Skewing by Inhibiting IL-4 Production from Basophils

We report that SHIP-/- mice, compared to SHIP+/+ mice, are Th2 skewed with elevated serum IgE and twice as many splenic CD4(+) Th2 cells that, when stimulated with anti-CD3, produce more IL-4 and less IFN-gamma. Exploring the reason for this Th2 skewing, we found that freshly isolated SHIP-/- splenic and bone marrow basophils are present in elevated numbers and secrete far more IL-4 in response to IL-3 or to Fc epsilon RI stimulation than do WT basophils. These SHIP-/- basophils markedly skew wildtype macrophage colony stimulating factor-derived macrophages toward an M2 phenotype, stimulate OT-II CD4(+) Th cells to differentiate into Th2 cells, and trigger SHIP+/+ B cells to become IgE-producing cells. All these effects are completely abrogated with neutralizing anti-IL-4 Ab. Exploring the cell signaling pathways responsible for hyperproduction of IL-4 by SHIP-/- basophils, we found that IL-3-induced activation of the PI3K pathway is significantly enhanced and that PI3K inhibitors, especially a p110 alpha inhibitor, dramatically suppresses IL-4 production from these cells. In vivo studies, in which basophils were depleted from mast cell-deficient SHIP+/+ and SHIP-/- mice, confirmed the central role that basophils play in the Th2 skewing of naive SHIP-deficient mice. Taken together, these studies demonstrate that SHIP is a potent negative regulator of IL-4 production from basophils and thus may be a novel therapeutic target for Th1- and Th2-related diseases. The Journal of Immunology, 2011, 186: 323-332.