Open Research Projects

Innate lymphoid cells, IL-22 and liver regeneration

Prinicipal Investigator

Scientific interest within the context of the graduate college:

We study development and function of the innate immune system, in particular of innate lymphoid cells (ILC). A current focus is to obtain a molecular understanding of how the innate immune system, by integrating environmental signals (such as those derived from nutrients, microbiota, circadian rhythm) contributes to tissue physiology. Recent studies have revealed ever more intriguing relationships between innate immune system components and basic developmental and biologic processes that are likely to reveal unsuspected pathways by which the immune system might be plumbed to improve health and healthspan. These lines of research have suggested new functions of the immune system for processes such as tissue homeostasis, morphogenesis, metabolism, regeneration and growth. Our research is developing by crossing boundaries of disciplines (immunology, microbiology, developmental biology, stem cell biology, nutrition sciences, tumor biology, regenerative medicine etc.) and is, by nature, highly interdisciplinary.

Project description:

Innate lymphoid cells (ILC) are tissue-resident innate lymphocytes that are involved in immunity to infections but are also deeply integrated in the regulation of tissue function. Based on our preliminary and on published data (Gronke, Nature 2019; Guendel, Immunity 2020; Diefenbach, Immunity 2020), we hypothesize that ILC regulates the function of non-hematopoietic cells to adapt organ function. In this project, we are exploring the role of ILC3 and of IL-22 in liver regeneration. Our preliminary data show that liver regeneration is dependent on IL-22. We have already obtained a high-resolution scRNAseq atlas of the regenerating liver of wildtype mice and of IL-22-deficient mice that reveal molecular network of IL-22-dependent regeneration. Three key questions will be addressed: (1) How is IL-22 production regulated during liver regeneration? Preliminary data reveal a neuron-ILC-hepatocyte axis that controls hepatocyte differentiation and renewal. (2) Which key regenerative pathways in hepatocytes are controlled by IL-22? Key data indicate that IL-22 signaling promotes a Wnt-driven regenerative program. (3) Can IL-22 be used to promote liver regeneration? We use mouse genetics combined with CRISPR/Cas9-driven lineage tracing/barcoding and high-dimensional single-cell genomics.

Application details

References

  1. Witkowski M, Tizian C, Ferreira-Gomes M, […], Radbruch A, Mashreghi MF, Diefenbach A. Untimely TGFβ responses in severe COVID-19 limit antiviral function of NK cells. Nature. 2021; 600:295-301. doi: 10.1038/s41586-021-04142-6.
  2. Schaupp L, Muth S, Rogell L, […], Schild H, Diefenbach A1,*, Probst HC*. Microbiota-induced tonic type I interferons instruct a poised basal state of dendritic cells. Cell. 2020; 181:1080-1096. doi: 10.1016/j.cell.2020.04.022. 1lead senior author; *equal contribution.
  3. Guendel F, Kofoed-Branzk M, Gronke K, […], Mashreghi MF, Kruglov AA, Diefenbach A. Group 3 innate lymphoid cells program a distinct subset of IL-22BP-producing dendritic cells demarcating solitary intestinal lymphoid tissues. Immunity. 2020; 53:1015-1032. doi: 10.1016/j.immuni.2020.10.012.
  4. Gronke K, Hernández PP, Zimmermann J, […], Glatt H, Triantafyllopoulou A, Diefenbach A. Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature. 2019; 566:249-253. doi: 10.1038/s41586-019-0899-7.
  5. Hernandez P, Mahlakoiv T, Yang I, […], Suerbaum S, Staeheli P, Diefenbach A. Interferon-λ and interleukin-22 cooperate for the induction of interferon-stimulated genes and control of rotavirus infection. Nat Immunol. 2015; 16:698-707. doi: 10.1038/ni.3180.