Development and function of the innate immune system
Developmental and Mucosal Immunology
Our current and future research is focused on a molecular understanding of how components of the innate immune system promotes tissue homeostasis by contributing to the adaptation of multicellular organisms to pernicious environments, such as those at barrier surfaces (e.g., intestine, skin).
We are addressing three major questions:
1. Transcriptional control of ILC development and function
Our lab has recently contributed to the discovery of innate lymphoid cells (ILCs), a group of tissue-resident innate lymphocytes located at border surfaces that release cytokines specifically acting on epithelial cells thereby contributing to tissue homeostasis and to the adaptation of the host in response to noxious compounds and tissue damage. A focus has been the analysis of transcriptional programs controlling lineage specification, commitment and function of ILCs. We recently identified a common, Id2-expressing progenitor to all ‘helper-like’ ILC lineages, the CHILP (Klose, Cell 2014). Our previous work has revealed that functional perturbations of ILC predispose to intestinal infections and to chronic inflammatory bowel diseases. It is likely, that such studies will identify new targets for the treatment of debilitating chronic inflammatory disorders.
2. The role of the indigenous microbiota in calibrating innate immunity
The role of environmental factors (microbiota, nutrients) for the formation of an effective and well calibrated innate immune response is recognized. Mononuclear phagocytes germ-free mice were unable to produce most pro-inflammatory cytokines (in particular type I IFN), and, consequently, germ-free mice were more susceptible to infections with viruses (Ganal, Immunity 2012). On a mechanistic level, we showed that signals of the microbiota are needed to remove a chromatin barrier required for the transcription of genes after ligation of pattern recognition receptors (PRR). Ongoing studies address the mechanistic underpinnings of this process as well as the microbiota-derived signals that tune mononuclear phagocyte responses. As many autoimmune diseases have a type I IFN signature, it is possible that dyscalibration of the mononuclear phagocytes by the microbiota may contribute to rheumatic diseases.
3. The role of nutrients for development and function of the innate immune system
Much has been learned about how the microbiota contributes to many aspects of host physiology. In contrast, the role of nutrients for development and function of the intestinal immune system has largely been a matter of speculation owing to the fact that molecular sensors of dietary molecules are widely unknown. Given the broad role of nutrients in metabolic diseases and the impact of intestinal cancer on human health, research into the question of how the power of nutrients can be harnessed for improving human health and for the prevention of disease is much warranted. We have recently found that the aryl hydrocarbon receptor (AhR), a transcription factor activated by small molecular ligands, is required for the development of innate immune system components by serving as a sensor for phytochemicals. Based on these preliminary data, we aim now to systematically define the role of diet-induced changes for the function and differentiation of mucosa-associated innate lymphocytes and to uncover how innate lymphocytes regulate epithelial adaptation by controlling niche support for intestinal epithelial stem cells.
Innate immune system
Innate Lymphoid Cells, ILC
Univ.-Prof. Dr. Andreas Diefenbach
Dr. Nora Kofoed-Branzk
Dr. Oliver Hoelsken
Dr. Irene Mattiola
Dr. Mario Witkowski
Karin Oberle, Lab manager
Publications 2016 and 2017
A. Original Articles
1. Original articles as first or senior/corresponding author
Herrtwich, L., I.Nanda, K.Evangelou, T.Nikolova, V.Horn, Sagar, D.Erny, J.Stefanowski, L.Rogell, C.Klein, K.Gharun, M.Follo, B.Kremer, M.Seidl, N.Münke, J.Sanger, M.Fliegauf, T.Aschman, D.Pfeifer, S.Sarrazin, M.Sieweke, D.Wagner, C.Dierks, T.Haaf, T.Ness, M.M.Zaiss, R.E.Voll, S.D.Deshmukh, M.Prinz, T.Goldmann, C.Hölscher, A.E.Hauser, A.J.Lopez-Contreras, D.Grün, V.Gorgoulis, A.Diefenbach*, P.Henneke, and A.Triantafyllopoulou*. 2016. DNA damage signaling instructs polyploid macrophage fate in granulomas. Cell. 167:1264-1280. *co-corresponding authors
(IF: 30.4, Times cited: 5)
Minton, K,. 2016. Macrophages: Granuloma macrophage differentiation. Nat Rev Immunol 15:402-403.
2. Publications as co-author
Nussbaum, K., S.Burkhard, I.Ohs, F.Mair, C.S.N.Klose, S.Arnold, A.Diefenbach, S.Tugues, and B.Becher. 2017. Tissue microenvironment dictates the fate and tumor-suppressive function of type 3 ILCs. J. Exp. Med. 214:2331-2347.
Bergmann, H., S.Roth, K.Pechloff, E.A.Kiss, S.Kuhn, M.Heikenwälder, A.Diefenbach, F.R.Greten, and J.Ruland. 2017. Card9-dependent IL-1 regulates IL-22 production from group 3 innate lymphoid cells and promotes colitis-associated cancer. Eur. J. Immunol. 47:1342-1353.
Van Acker, A., K.Gronke, A.Biswas, L.Martens, Y.Saeys, J.Filtjens, S.Taveirne, E.Van Ammel, T.Kerre, P.Matthys, T.Taghon, B.Vandekerckhove, J.Plum, I.R.Dunay, A.Diefenbach, and G.Leclercq. 2017. A murine intestinal intraepithelial NKp46-negative innate lymphoid cell population characterized by group 1 properties. Cell Reports. 19:1431-1443.
Schwartz, C., J.U.Eberle, T.Hoyler, A.Diefenbach, M.Lechmann, and D.Voehringer. 2016. Opposing functions of thymic stromal lymphopoietin-responsive basophils and dendritic cells in a mouse model of atopic dermatitis. J Allergy Clin Immunol. 138:1443-1446.
B. Review Articles
Britanova, L., and A.Diefenbach. 2017. Interplay of innate lymphoid cells and the microbiota. Immunol Rev. 279:36-51
Diefenbach, A., M.Colonna, and C.Romagnani. 2017. The ILC World Revisited. Immunity. 46:327-332.
(IF: 22.8; Times cited: 90)
Gronke, K., M.Kofoed-Nielsen, and A.Diefenbach. 2016. Innate Lymphoid Cells, Precursors and Plasticity. Immunol Lett. 179:9-18.
(IF: 2.9; Times cited: 4)