SHIP-Deficient Dendritic Cells, Unlike Wild Type Dendritic Cells, Suppress T Cell Proliferation via a Nitric Oxide-Independent Mechanism

Background: Dendritic cells (DCs) not only play a crucial role in activating immune cells but also suppressing them. We recently investigated SHIP’s role in murine DCs in terms of immune cell activation and found that TLR agonist-stimulated SHIP2/2 GM-CSF-derived DCs (GM-DCs) were far less capable than wild type (WT, SHIP+/+) GM-DCs at activating T cell proliferation. This was most likely because SHIP2/2 GM-DCs could not up-regulate MHCII and/or co-stimulatory receptors following TLR stimulation. However, the role of SHIP in DC-induced T cell suppression was not investigated. Methodology/Principal Findings: In this study we examined SHIP’s role in DC-induced T cell suppression by co-culturing WT and SHIP2/2 murine DCs, derived under different conditions or isolated from spleens, with aCD3+ aCD28 activated WT T cells and determined the relative suppressive abilities of the different DC subsets. We found that, in contrast to SHIP+/+ and 2/2 splenic or Flt3L-derived DCs, which do not suppress T cell proliferation in vitro, both SHIP+/+ and 2/2 GM-DCs were capable of potently suppressing T cell proliferation. However, WT GM-DC suppression appeared to be mediated, at least in part, by nitric oxide (NO) production while SHIP2/2 GM-DCs expressed high levels of arginase 1 and did not produce NO. Following exhaustive studies to ascertain the mechanism of SHIP2/2 DC-mediated suppression, we could conclude that cell-cell contact was required and the mechanism may be related to their relative immaturity, compared to SHIP+/+ GM-DCs. Conclusions: These findings suggest that although both SHIP+/+ and 2/2 GM-DCs suppress T cell proliferation, the mechanism(s) employed are different. WT GM-DCs suppress, at least in part, via IFNc-induced NO production while SHIP2/2 GM-DCs do not produce NO and suppression can only be alleviated when contact is prevented.