SHIP-deficient dendritic cells, unlike wild type dendritic cells, suppress T cell proliferation via a nitric oxide-independent mechanism

• Published in: PloS one 2011-07, Vol.6 (7), p.e21893-e21893
• Main Authors: Antignano, Frann, Hamilton, Melisa, Patterson, Scott, Ho, Victor, Cohen, Carla, Levings, Megan K, Krystal, Gerald
• Format: Article
• Language: English
• Subjects: Amino Acids - metabolism; Animals; Antigens; Apoptosis; Arginase; Arginase - metabolism; Biology; Bone marrow; Cancer; Cell activation; Cell adhesion; Cell Adhesion - drug effects; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Coculture Techniques; Cytokines; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - enzymology; FLT3L protein; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Immune system; Immunosuppression; Immunotherapy; Inositol Polyphosphate 5-Phosphatases; Interferon-gamma - metabolism; Kinases; Laboratories; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes T; Medicine; Mice; Models, Immunological; Nitric oxide; Nitric Oxide - metabolism; Phosphoric Monoester Hydrolases - deficiency; Phosphoric Monoester Hydrolases - metabolism; Receptors; Ships; Spleen; T cell receptors; T cells; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0021893

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 SHIP-/- 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 SHIP-/- 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. In this study we examined SHIP's role in DC-induced T cell suppression by co-culturing WT and SHIP-/- murine DCs, derived under different conditions or isolated from spleens, with αCD3+ αCD28 activated WT T cells and determined the relative suppressive abilities of the different DC subsets. We found that, in contrast to SHIP+/+ and -/- splenic or Flt3L-derived DCs, which do not suppress T cell proliferation in vitro, both SHIP+/+ and -/- 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 SHIP-/- GM-DCs expressed high levels of arginase 1 and did not produce NO. Following exhaustive studies to ascertain the mechanism of SHIP-/- 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. These findings suggest that although both SHIP+/+ and -/- GM-DCs suppress T cell proliferation, the mechanism(s) employed are different. WT GM-DCs suppress, at least in part, via IFNγ-induced NO production while SHIP-/- GM-DCs do not produce NO and suppression can only be alleviated when contact is prevented.