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Projects

Phosphatidylserine and "turning off" of cytotoxic lymphocytes

One of the problems with trying to develop immune responses to tumors is that the tumors are often "tolerized" by the immune system. As mentioned previously, this may be due in part to DC producing TGFβ upon interaction with phosphatidylserine (PS) on apoptotic cells. However, many studies have found that increased numbers TGFβ expressing lymphocytes in tumors are correlated with poor prognosis. For NK cells, TGFβ can reduce the expression of NKG2D on the NK cell surface, cytokine production and cytotoxicity. CD8+ T cells are similarly affected by TGFβ. However, it is unclear whether the T cells and NK cells which also express PS receptors can make TGFβ directly upon interaction with PS on apoptotic tumor cells. Thus this study continues to investigate what role PS plays in inducing tumor "tolerance" in NK cells and T cells.

Immuno-evasion by infectious pathogens

While studying NK cell interactions with dendritic cells, we have found novel techniques of immuno-evasion by the parasite Toxoplasma gondii. In contrast to previous studies where viral and bacterial infected dendritic cells are protected from NK cell mediated lysis, Toxoplasma gondii infected dendritic become more sensitive to NK cells, allowing the parasite to exit the dendritic cell and infect surrounding NK cells. One effect of NK cells infection by Toxoplasma gondii, is that they no longer are cytotoxic and no longer produce IFNγ and other proinflammatory cytokines, essential in the defence against Toxoplasma gondii. Future plans will examine how Toxoplasma gondii can control the production of inflammatory cytokines in NK cells and identify target molecules by gene array. These studies may identify new molecules that could be used to treat inflammatory responses.

NK cell recruitment and activation by dendritic cells in vivo

We have demonstrated that plasmacytoid dendritic cells either generated in culture with flt3L or purified from spleens stimulated with the CpG can induce NK cell migration to the peritoneal cavity and the activation of NK cells as measured by cytotoxicity and IFNγ production. However in the course of these studies, it was noticed that the different dendritic cell subsets appeared to induce NK cell migration using different chemokines and differential levels of activation. We are now investigating the relative role of the CD8+ and CD8- dendritic cells in the activation of NK cells.