Immune Responses in Cancer
It is increasingly recognized that various types of immune cells play important roles in protecting humans from cancer. Dendritic cells (DCs), in particular, occupy a critical position in regulating immune responses, as they have the potential to translate signals issuing from innate immune cells into productive adaptive immune responses. Upon direct contact with DCs, naïve CD4+ T cells and CD8+ T cells can undergo differentiation into specific T cell subsets. These different types of effector T cells are specialized to destroy tumor cells and to protect the host against invading pathogens.
Regulatory T cells are crucial for maintaining self-tolerance, and they can suppress effector T cell functions and block antitumor-immunity. Because immature DCs promote the generation of regulatory T cells, whereas activated/mature DCs can launch the differentiation of naïve T cells into effector T cells, DCs are critically involved in balancing regulatory versus effector T cell functions.
Our current research focuses on the molecular mechanisms that govern the transition of DCs from the immature state to the mature state. We investigate the process of DC-maturation and the mechanisms that counteract this process. By using a combination of immunological and molecular biological methods, we analyze the state of DC maturation and investigate the properties of those cells to determine the outcome of the respective T cell responses.
Maier E., Mittermaier M., Ess S., Neuper T., Schmiedlechner A., Duschl A., Horejs-Hoeck J. Prerequisites for functional Interleukin 31 Signaling and Feedback Regulation by Suppressors of Cytokine Signaling (SOCS), 2015, J Biol Chem. Oct 9;290(41):24747-59. doi: 10.1074/jbc.M115.661306
Maier E., Werner D., Duschl A, Bohle B., Horejs-Hoeck J. Human Th2 but not Th9 cells release IL-31 in a STAT6/NF-κB-dependent way. 2014, J Immunol. Jul 15;193(2):645-54. doi: 10.4049/jimmunol.1301836.
Schwarz H, Posselt G, Wurm P, Ulbing M, Duschl A, Horejs-Hoeck J. TLR8 and NOD signaling synergistically induce the production of IL-1β and IL-23 in monocyte-derived DCs and enhance the expression of the feedback inhibitor SOCS2. 2013. Immunobiology. Apr;218(4):533 42. doi:10.1016/j.imbio.2012.06.007
Posselt G, Schwarz H, Duschl A, Horejs-Hoeck J. Suppressor of Cytokine Signalling 2 (SOCS2) is a feedback inhibitor of TLR induced activation in monocyte derived dendritic cells. 2011. J. Immunol., 187:2875-84. doi: 10.4049/jimmunol.1101044
Maier E, Hebenstreit D, Posselt G, Hammerl P, Duschl A, Horejs-Hoeck J. Inhibition of suppressive T Cell Factor 1 (TCF-1) isoforms in naive CD4+ T cells is mediated by IL-4/STAT6 signaling. 2010 J. Biol. Chem. 286:919-928. doi: 10.1074/jbc.M110.
Jutta Horejs-Hoeck, PhD
Department of Biosciences
University of Salzburg
Dendritic cells (DCs) determine the outcome of T cell responses
The conversion of an immature DC into a mature DC is promoted by (micro)environmental factors such as danger-associated patterns (DAMPS), pathogen-associated patterns (PAMPs) and cytokines, which are recognized by the immature DC via the respective receptors (Toll-Like Receptors, Nod-Like Receptors and cytokine receptors). Upon maturation, DCs express a number of costimulatory molecules, including MHCI and MHCII, CD80/CD86, CD40, PDL-1, PDL-2, that contribute to the differentiation of cytotoxic T cells (CTL) or specific T helper cell subsets (TH1, TH2, TH9, TH17 TH22, Treg). Functional responses of effector T cells can be repressed by regulatory T cells (Treg).