Benedict Chambers group
The main focus of our research is to investigate the role of natural killer (NK) cells in the development of adaptive immune responses. The research focuses along two lines. (1) The interaction between dendritic cells (DC) and NK cells. (2) How NK cells can affect T and B cell mediated responses by direct physical interaction.
In particular, we are looking at the role of TRAIL in the elimination of DC in vivo and the role of 2B4 (CD244) on NK cells in the stimulation of T cells. How NK cells interact with DC or cells of the adaptive immune system has implications for the generation of a successful immune response aimed at eradication of infections or tumors. The studies also have relevance for the uncontrolled immune reactions occurring during autoimmune reactions and during allergic responses.
Keywords: NK cell, T cell, cellular, cytotoxicity, cancer, virus, toxoplasma
|Benedict Chambers, Group Leader, PhD. Phone: +46-8-52486216|
|Anna Maria Georgoudaki, PhD|
|Jonas Fuks, PhD|
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.
Influenza-Activated ILC1s Contribute to Antiviral Immunity Partially Influenced by Differential GITR Expression.
Front Immunol 2018 ;9():505
Voltage-dependent calcium channel signaling mediates GABAA receptor-induced migratory activation of dendritic cells infected by Toxoplasma gondii.
PLoS Pathog. 2017 Dec;13(12):e1006739
The effects of hepatitis C virus core protein on functional responses in the NK cell line YTS.
Scand. J. Immunol. 2012 Jan;75(1):54-60
Migratory activation of primary cortical microglia upon infection with Toxoplasma gondii.
Infect. Immun. 2011 Aug;79(8):3046-52
Plasmacytoid dendritic cell-induced migration and activation of NK cells in vivo.
Eur. J. Immunol. 2010 Aug;40(8):2155-64
Heterogeneous expression of the adhesion receptor CD226 on murine NK and T cells and its function in NK-mediated killing of immature dendritic cells.
J. Leukoc. Biol. 2009 Jul;86(1):91-101
Transmission of Toxoplasma gondii from infected dendritic cells to natural killer cells.
Infect. Immun. 2009 Mar;77(3):970-6
Human cytomegalovirus-derived protein UL18 alters the phenotype and function of monocyte-derived dendritic cells.
J. Leukoc. Biol. 2008 Jan;83(1):56-63
Critical role of Qa1b in the protection of mature dendritic cells from NK cell-mediated killing.
Scand. J. Immunol. 2008 Jan;67(1):30-6
Induction of protective CTL immunity against peptide transporter TAP-deficient tumors through dendritic cell vaccination.
Cancer Res. 2007 Sep;67(18):8450-5
NK cells stimulate proliferation of T and NK cells through 2B4/CD48 interactions.
J. Immunol. 2004 Jul;173(1):174-80
NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy.
J. Immunol. 2004 Jan;172(1):123-9
We always want to get in touch with talented potential co-workers. If you are interested in doing research within our group, as a degree project or as a researcher, please contact the group leader Benedict Chambers.