Mechanisms that restrict the immune response are critical to avoid damaging reactivity that can lead to allergies and inflammatory responses or, in more severe cases, to lethal autoimmune diseases. Our goal is to understand mechanisms that downregulate the immune response, control lymphocyte proliferation and antibody production. With this intention we initiated a study of the negative regulatory pathway mediated by the inositol phosphatase SHIP. Absence of SHIP results in reduced viability of the mice due to a myeloproliferative-like syndrome, with profound splenomegaly and massive myeloid cell accumulation in the lungs. The very pleiotropic phenotype of SHIP-/- mice reflects the fact that SHIP is a general down-modulator of growth factor, cytokine, Fc and antigen receptor activity. To get a more precise idea of the in vivo function of SHIP in specific cells while avoiding pleiotropic interactions, we have begun to characterize tissue-specific or inducible SHIP mutations in mice. We have generated loxP-flanked SHIP mice that can be crossed to several Cre recombinase-expressing mice. In collaboration with Jeff Ravetch we have determined the essential role of SHIP in the formation of the splenic marginal zone utilizing mice with macrophage specific deletion of SHIP. We are now characterizing the functional role of SHIP in T lymphocyte selection, tolerance as well as the effects of mast cell-specific deletion of SHIP.
