SHIP-deficient dendritic cells suppress T cell proliferation via a nitric oxide independent mechanism (91.9)

Abstract

Abstract Dendritic cells (DCs) are potent stimulators of the immune system but can also be powerful inducers of tolerance. Previous studies have shown that myeloid DC precursors are capable of suppressing T cell proliferation through a contact and nitric oxide (NO) -dependent mechanism. In addition, GM + IL-4, but not Flt3L, -derived DCs have been reported to suppress T cell proliferation by inducing T cell apoptosis. The SH2-containing inositol 5'-phosphatase (SHIP) is a potent suppressor of the PI3K pathway with known functions in regulating myeloid cell development and survival. However, little is known of SHIP's role in the suppressive ability of DC subsets. In this study we co-cultured polyclonally activated T cells with bone marrow derived DCs or DCs isolated from the spleens of WT and SHIP-/- mice to determine SHIP's role in DC-induced T cell suppression. We found that both WT and SHIP-deficient DCs derived with GM-CSF ± IL-4 profoundly suppress T cell proliferation while Flt3L-derived and splenic DCs do not. The mechanism of suppression proved to be contact dependent for WT and SHIP-deficient GM-CSF DCs. However, unlike WT, SHIP-deficient DCs do not produce detectable levels of NO. These results suggest a novel mechanism of myeloid DC-induced T cell suppression at work in SHIP-deficient DCs. This research is funded by an NCIC grant held by GK.