Mechanisms controlling immune responses
Previous and Current Research
The group focuses on endogenous mechanisms that control (i.e. limit) immune responses in vivo and thereby prevent inflammatory disease caused by immune-mediated damage to host tissues. Malignant tumors corrupt such immunosuppressive principles to protect themselves against anti-tumor immunity.
1. Interleukin-10-mediated control of immune response
The destructive potential of the weapons of the immune system pose an enormous threat to the tissues of the host. In order to prevent autoimmunity and “collateral damage” to host tissues in the course of responses to pathogens, innate and adaptive immunity are subject to stringent control mechanisms. One of the key factors controlling immune responses is the cytokine IL-10. IL-10-deficient mice mount exaggerated immune responses, which can cause severe or even lethal immunopathology. We use the Cre-loxP recombination system to generate mice with cell type-specific inactivation of the IL-10 gene in order to identify cellular sources of the cytokine that are relevant in various situations of immune challenge. The results we obtained so far show that the cellular source of IL-10 critically determines it’s biological effects.
IL-10 not only controls responses to infections but is also important in the regulation of anti-tumor immunity. It may be pivotal in the tumor-induced suppression of anti-tumor T cell responses. In order to identify the cellular sources of IL-10 relevant in suppression of anti-tumor immunity, we are now investigating our cell type-specific IL-10 knock out mouse strains for alterations of malignant growth.
2. Role of mast cells in adaptive immune responses
Besides their well-known function as effector cells in allergic responses, mast cells were reported to play a critical role in innate immunity and to exert important stimulatory but also suppressive functions in adaptive immune responses. We have generated new genetic tools for the analysis of in vivo mast cell functions that allow for cell type-specific inactivation (“knock out“) of target genes selectively in mast cells by Cre loxP-mediated recombination. The new mouse strains are ideally suited to settle fundamental questions regarding the biology of mast cells and their functions in the immune system. We are particularly interested in the in vivo relevance of mast cell-derived immunostimulatory or suppressive cytokines like TNF-α, IL-10 or TGF-β.
A striking finding in many malignant tumors is a massive accumulation of mast cells. The reason for their presence and their functional roles in malignant growth remain unclear. Several studies suggested that mast cells may be essential for cancerogenesis and tumor progression. We are currently employing our new genetic tools for mast cell-specific inactivation of loxP-flanked genes and for inducible ablation of mature mast cells in adult animals to clarify the roles mast cells play in neoplastic disease. In particular, we are addressing the relevance of mast cell-derived immunosuppressive cytokines (IL-10 and TGF-β).
Future Projects and Goals
Our goals are to better understand mechanisms that control immune responses. We hope to design new therapeutic approaches to suppress the deregulated immune response in inflammatory diseases. Since tumors use immunosuppressive mechanisms of the host to protect themselves against the immune response, we also hope to find ways to improve cancer therapy.
Methodological and Technical Expertise
- Generation of BAC transgenic and gene targeted mice
- mouse phenotyping (including histology)
- Flow cytometric analysis and cell sorting
- Mouse bone marrow transplantation
- 2-photon based in vivo imaging of various mouse organs
Rubtsov YP, Rasmussen JP, Chi YE, Fontenot J, Castelli L, Ye X, Siewe L, Roers A, Müller W, Rudensky AY
IL-10 produced by regulatory T cells contributes to their suppressor function by limiting inflammation at environmental interfaces.
Immunity, 28: 546–58 (2008)
Scholten J, Hartmann K, Gerbaulet A, Krieg T, Müller W, Testa G, Roers A
Mast cell-specific Cre/loxP-mediated recombination in vivo.
Transgenic Research, 17: 307–315 (2007)
Eming SA, Werner S, Bugnon P, Hua J, Davidson JM, Krieg T, Roers A
Accelerated wound closure in mice deficient for interleukin-10.
Am J Pathol 170: 188–202 (2007)
Siewe L, Bollati-Fogolin M, Wickenhauser C, Krieg T, Muller W, Roers A
Interleukin-10 derived from macrophages and/or neutrophils regulates the inflammatory response to LPS but not the response to CpG DNA.
Eur J Immunol 36: 3248–55 (2006)
Roers, A., Siewe, L., Strittmatter, E., Deckert, M., Schlüter, D., Stenzel, W., Gruber, A.D., Krieg, T., Rajewsky, K., Müller, W
T cell-specific inactivation of the interleukin-10 gene in mice results in enhanced T cell responses but normal innate responses to LPS or skin irritation.
J Exp Med 200: 1289-97 (2004)