The IL-33 Receptor.

We have identified the orphan receptor T1/ST2 as functionally relevant marker-molecule of Th2 cells (Löhning 1998, Meisel 2001). T1/ST2 is the ligand-binding chain of the IL-33R. Our current interest is in the interaction of the IL-33R with other membane-bound receptors. We have shown that the IL-33R interacts with heterologous receptors such as c-Kit (the receptor for stem cell factor) (Drube 2010). This cross-activtion enables c-Kit to activate signaling molecules which are downstream of the IL-33R. Integration of these different signalling pathways results in synergistically enhanced effector functions (Drube 2010) and allow spatio-temporal control of cellular effector functions (Drube 2015, Drube 2016). In a project funded by the DFG (hier Link zu GEPRIS, Sebastian) we are currently investigating the molecular mechanisms of the interaction between the IL-33R and c-kit. Collaborating with the Zaiss Lab in Edingburgh we have recently shown that the interaction between T1/ST and the epidermal growth factor receptor (EGFR) enables Th2 cells in inflamed tissue to exert effector functions independently of local TCR-stimulation (Minutti 2017).

Collaboration Partners

Dr. Dietmar Zaiss, Institute of Immunology and Infection Research, Universtiy of Edinburgh

Dr. Anne Dudeck Magdeburg, Institute for Molecular and Clinical Immunology, University Hospital Magdeburg

10 papers on the IL-33R

Göpfert, C., N. Andreas, F. Weber, N. Hafner, T. Yakovleva, M. Gaestel, T. Kamradt, and S. Drube. 2018.

The p38-MK2/3 Module Is Critical for IL-33-Induced Signaling and Cytokine Production in Dendritic Cells.

Journal of immunology 200:1198-1206.

Minutti, C.M., S. Drube, N. Blair, C. Schwartz, J.C. McCrae, A.N. McKenzie, T. Kamradt, M. Mokry, P.J. Coffer, M. Sibilia, A.J. Sijts, P.G. Fallon, R.M. Maizels, and D.M. Zaiss. 2017.

Epidermal Growth Factor Receptor Expression Licenses Type-2 Helper T Cells to Function in a T Cell Receptor-Independent Fashion.

Immunity 47:710-722 e716.

Drube, S., F. Kraft, J. Dudeck, A.L. Muller, F. Weber, C. Gopfert, I. Meininger, M. Beyer, I. Irmler, N. Hafner, D. Schutz, R. Stumm, T. Yakovleva, M. Gaestel, A. Dudeck, and T. Kamradt. 2016.

MK2/3 Are Pivotal for IL-33-Induced and Mast Cell-Dependent Leukocyte Recruitment and the Resulting Skin Inflammation.

Journal of immunology 197:3662-3668.

Drube, S., F. Weber, C. Gopfert, R. Loschinski, M. Rothe, F. Boelke, M.A. Diamanti, T. Lohn, J. Ruth, D. Schutz, N. Hafner, F.R. Greten, R. Stumm, K. Hartmann, O.H. Kramer, A. Dudeck, and T. Kamradt. 2015.

TAK1 and IKK2, novel mediators of SCF-induced signaling and potential targets for c-Kit-driven diseases.

Oncotarget 6:28833-28850.

Drube, S., F. Weber, R. Loschinski, M. Beyer, M. Rothe, A. Rabenhorst, C. Gopfert, I. Meininger, M.A. Diamanti, D. Stegner, N. Hafner, M. Bottcher, K. Reinecke, T. Herdegen, F.R. Greten, B. Nieswandt, K. Hartmann, O.H. Kramer, and T. Kamradt. 2015.

Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells.

Oncotarget 6:5354-5368.

Kamradt, T., and S. Drube. 2013.

A complicated liaison: IL-33 and IL-33R in arthritis pathogenesis.

Arthritis research & therapy 15:115.

Zaiss, M.M., M. Kurowska-Stolarska, C. Bohm, R. Gary, C. Scholtysek, B. Stolarski, J. Reilly, S. Kerr, N.L. Millar, T. Kamradt, I.B. McInnes, P.G. Fallon, J.P. David, F.Y. Liew, and G. Schett. 2011.

IL-33 shifts the balance from osteoclast to alternatively activated macrophage differentiation and protects from TNF-alpha-mediated bone loss.

Journal of immunology 186:6097-6105.

Drube, S., S. Heink, S. Walter, T. Lohn, M. Grusser, A. Gerbaulet, L. Berod, J. Schons, A. Dudeck, J. Freitag, S. Grotha, D. Reich, O. Rudeschko, J. Norgauer, K. Hartmann, A. Roers, and T. Kamradt. 2010.

The receptor tyrosine kinase c-Kit controls IL-33 receptor signaling in mast cells.

Blood 115:3899-3906.

Meisel, C., K. Bonhagen, M. Lohning, A.J. Coyle, J.C. Gutierrez-Ramos, A. Radbruch, and T. Kamradt. 2001.

Regulation and function of T1/ST2 expression on CD4+ T cells: induction of type 2 cytokine production by T1/ST2 cross-linking.

Journal of immunology 166:3143-3150.

Löhning, M., A. Stroehmann, A.J. Coyle, J.L. Grogan, S. Lin, J.C. Gutierrez-Ramos, D. Levinson, A. Radbruch, and T. Kamradt. 1998.

T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function.

Proceedings of the National Academy of Sciences of the United States of America 95:6930-6935.