Research

ILC3 as regulators of intestinal organ hypertrophy in response to increased metabolic demands during pregnancy and lactation

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, contributes to tissue physiology and health. 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 health span. 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:

Based on our data, we hypothesize that ILC3 play an important role in directly instructing adaptation of the intestinal organ to changing metabolic needs by affecting programs in epithelial stem cells or their immediate progeny. Available data has interrogated the role of ILC3: stem cell modules in the context of intestinal damage. We wondered if ILC3 are involved in more physiological adaptative processes. One of the biggest challenges to metabolic demands in life is pregnancy. During gestation and lactation, the female organism undergoes major physiological changes to accommodate the developing offspring prominent among them considerable growth of the crypt-villus axis of the small intestine. We have recently developed a sophisticated method to record crypt-villus length and noted that mice lacking ILC3 (i.e., Rorc(gt)Gfp/Gfp mice) do not show pregnancy and lactation-induced epithelial hypertrophy. Interestingly, such absence of intestinal growth led to reduced caloric absorption by enterocytes and reduced caloric content of breast milk.

We hypothesize that ILC3 act on intestinal stem cells enhancing differentiation of enterocytes for increased nutrient absorption. Our research may provide a novel conceptual framework of how tissue and metabolic adaptation can be sustained by ILC3 that may dynamically adjust epithelial cell function to a variety of physiological demands.

Our major goals are (1) to define the role of ILC3 in pregnancy and lactation-induced epithelial hypertrophy on a molecular level, (2) to analyze the impact of ILC3 on stem cell representation, niche population dynamics using stochastic multi-color fate labelling and (3) to understand how ILC3 regulate epithelial cell metabolism and tissue growth during pregnancy and lactation.

Application details

References

  1. 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.
  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. 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.
  4. Klose CSN, Flach M, Möhle L, […], Dunay IR, Tanriver Y, Diefenbach A. Differentiation of type 1 ILCs from a common progenitor to helper-like innate lymhoid cell lineages. Cell. 2014; 157:340-356. doi: 10.1016/j.cell.2014.03.030.
  5. Klose CSN, Kiss EA, Schwierzeck V, […], Waisman A, Tanriver Y, Diefenbach A. A T-bet gradient controls the fate and function of CCR6 RORγt+ innate lymphoid cells. Nature. 2013, 494:261-265. doi: 10.1038/nature11813.