The Diefenbach laboratory studies development and function of the innate immune system. Their current and future research is focused on a molecular understanding of how 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).
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 interleukin 7 receptor-expressing, ‘helper-like’ ILC lineages, the CHILP. Interestingly, the CHILP differentiated into ILC2 and ILC3 lineages but not into conventional natural killer (cNK) cells. Instead, the CHILP gave rise to a peculiar NKp46+ IL-7Rα+ ILC lineage that required T-bet for specification and was distinct of cNK cells or other ILC lineages, the enigmatic ILC1. Previous work of the group has revealed that functional perturbations of ILC predispose to intestinal infections and to chronic inflammatory bowel diseases. It is likely, that such studies will expose primordial functions of the immune system and will identify new targets for the treatment of debilitating chronic inflammatory disorders.
Hernandez, P., T.Mahlakoiv, I.Yang, V.Schwierzeck, N.Nguyen, F.Guendel, K.Gronke, B.Ryffel, C.Hoelscher, L.Dumoutier, J.C. Renauld, S.Suerbaum, P.Staeheli, A.Diefenbach. 2015. Interferon-λ and interleukin-22 cooperate for the induction of interferon-stimulated genes and control of rotavirus infection. Nature Immunology. 16:698-707.
Klose, C.S.N., M.Flach, L.Möhle, L.Rogell, T.Hoyler, C.Fabiunke, K.Ebert, D.Pfeifer, V.Sexl, D.Fonseca Pereira, R.G.Domingues, H.Veiga-Fernandes, S.Arnold, I.R.Dunay, Y.Tanriver, and A.Diefenbach. 2014. Differentiation of type 1 ILCs from a common progenitor to helper-like innate lymhoid cell lineages. Cell. 157:340-356.
Diefenbach, A., Colonna, M., and Koyasu, S. 2014. Development, differentiation and diversity of innate lymphoid cells. Immunity. 41:354-365.
Klose, C.S.N., E.A.Kiss, V.Schwierzeck, K.Ebert, T.Hoyler, Y.d’Hargues, N.Göppert, A.L.Croxford, A.Waisman, Y.Tanriver, and A.Diefenbach. 2013. A T-bet gradient controls the fate and function of CCR6- RORγt+ innate lymphoid cells. Nature. 494:261-265.
Hoyler, T., C.S.N.Klose, A.Souabni, A.Turqueti-Neves, D.Pfeifer, E.L.Rawlins, D.Voehringer, M.Busslinger, and A.Diefenbach. 2012. The transcription factor Gata3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity. 37:634-648.
Vonarbourg, C., A.Mortha, V.L.Bui, P.Hernandez, E.A.Kiss, T.Hoyler, M.Flach, B.Bengsch, R.Thimme, C.Hölscher, M.Hönig, U.Pannicke, K.Schwarz, C.F.Ware, D.Finke, and A.Diefenbach. 2010. Regulated expression of nuclear receptor RORγt+ confers distinct functional fates to NK cell receptor-expressing RORγt+ innate lymphocytes. Immunity. 33:736-751.
Sanos, S.L., V.L.Bui, A.Mortha, K.Oberle, C.Heners, C.Johner, and A.Diefenbach. 2009. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nature Immunology. 10:83-91.
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. Our recent work has identified an important role of the microbiota for the functional calibration of mononuclear phagocytes throughout the body. Interestingly, mononuclear phagocytes from germ-free mice were unable to produce type I interferons and other inflammatory cytokines in response to pathogen-associated molecular patterns (PAMPs). Therefore, germ-free mice were unable to control viral infections. Such inability to produce cytokines reflected the failure of transcription factors activated by PAMPs (e.g., NF-κB, IRF3) to gain access to the promoter and enhancer regions of the relevant genes. These data revealed an important and previously unrecognized role of the microbiota in poising proinflammatory gene expression by introducing epigenetic changes required for the punctual expression of cytokines needed for the protection against pathogens. Poising of gene expression within mononuclear phagocytes is likely to commence with colonization of newborns by an increasingly complex microbiota. It is intriguing to speculate that colonization of mucosal surfaces controls the development of a myeloid functional program designed to manage postnatal exposure to microbes and pathogens. During fetal development, the main function of macrophages is the removal of apoptotic cells generated in developmental processes. Expression of inflammatory genes by fetal mononuclear phagocytes may not be desirable. However, after birth, when mucosal surfaces become entry ports for pathogens, inflammatory genes are necessary to coordinate powerful and effective antimicrobial immunity. The commensal microbiota induces genome-wide changes, likely at the level of chromatin. This leads to poising of inflammatory gene expression, thereby calibrating mononuclear phagocytes at sterile, non-mucosal sites to respond promptly to pathogens.
Ganal, S.C., S.L.Sanos, C.Kallfass, K.Oberle, C.Johner, C.Kirschning, S.Lienenklaus, S.Weiss, P.Staeheli, P.Aichele, and A.Diefenbach. 2012. Priming of natural killer cells by non-mucosal mononuclear phagocytes requires instructive signals from the commensal microbiota. Immunity. 37:171-186.
Lucas, M., W.Schachterle, K.Oberle, P.Aichele, and A.Diefenbach. 2007. Dendritic Cells Prime Natural Killer Cells by trans-Presenting Interleukin 15. Immunity. 26:503-517.
The role of nutrients for development and function of the innate immune system
Much has been learned about how the microbiota contributes to intestinal homeostasis through the identification of host molecules sensing microbiota and even of specific microbiota controlling distinct aspects of immune cell function. In contrast to the role of the microbiota, 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. The AhR serves as a sensor for dietary AhR ligands that are contained in high concentrations in vegetables of the Brassicaceae family (e.g., broccoli, Brussel sprouts). Specifically, a subset of innate lymphocytes (ILC) referred to as lymphoid tissue inducer (LTi) cells, a subset of ILC3s that is involved in maintaining epithelial barrier function and resistance to intestinal infections, required diet-induced AhR signals for its maintenance and expansion. Consequently, mice lacking AhR expression in ILC3s lacked the formation of postnatally forming cryptopatches and isolated lymphoid follicles and were highly susceptible against Citrobacter rodentium, a mouse model of attaching-and-effacing infections. The data established the first molecular link between diets and the development of immune system components. Based on these preliminary data, the groups aims 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.
Kiss, E.A., C.Vonarbourg, S.Kopfmann, E.Hobeika, D.Finke, C.Esser, and A.Diefenbach. 2011. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science. 334:1561-1565.
European Research Council (ERC)
Deutsche Forschungsgemeinschaft (DFG)