Open Research Projects

Dissecting tissue-homeostatic functions of group 2 innate lymphoid cells using novel genetic tools

Prinicipal Investigator

Dr. Christoph Klose
Prof. Dr. Andreas Diefenbach

Scientific interest within the context of the graduate college:

Type 2 Inflammation, innate lymphoid cells, tissue-homeostasis, neuro-immune interactions.

Project description:

Type 2 immune responses promote tissue homeostasis as well as tissue remodeling and protect against infections with macroparasites but can become detrimental when triggered against non-infectious environmental stimuli.1 The cytokines IL-25, IL-33, and TSLP are strong activators of type 2 inflammation in tissues via stimulation of group 2 innate lymphoid cells (ILC2s) and other innate immune cells, such as eosinophils, mast cells, basophils, and alternatively activated macrophages resulting in a cytokine milieu, which promotes differentiation of T helper 2 cells and secretion of immunoglobulin E.1,2 Although ILC2s become quickly activated, the precise role in orchestrating type 2 immune responses remains elusive due to the limitations in specifically targeting this population in the presence of adaptive immune cells because of the large overlap in expression of ILC2s with T cells and other immune cells.

To guide over this major limitation in the field, we could recently generate and evaluate a model to specifically deplete ILC2s based on the Nmur1 promoter. Using this model, we could recently show that ILC2s are the major determinate of eosinophil homeostasis in tissues if ILC2 are genetically ablated from the beginning. Exploiting the possibilities of this newly generated tool, we now aim to deplete ILC2 after development (using antibody depletion against ectopically expressed hCD2) or to pharmacologically modulate ILC2 (using ectopically expressed designer drug receptors) functions. The downstream effector functions will also be explored by conditional deletion of interleukin 5 in ILC2. Our working hypothesis proposes that ILC2s could be a promising target via pharmacological modulation or antibody-mediated depletion because of their tissue-homeostatic functions, namely regulation of eosinophils in tissue via IL-5. The models to test this hypothesis are available in our lab, and the techniques are carried out on a daily basis without the requirement to establish novel methods from scratch. Delineating the regulation of type 2 immune responses by ILC2s will be key to understand how type 2 immune responses are orchestrated. Using both focused and global experimental approaches our research has the potential to discover novel molecular pathways, which can be harnessed for the maintenance of homeostasis and prevention of chronic inflammation.

Application details

References

  1. Palm NW, Rosenstein RK, Medzhitov R. Allergic host defences. Nature. 2012; 484:465-472. doi: 10.1038/nature11047.
  2. Klose CSN, Artis D. Innate lymphoid cells control signaling circuits to regulate tissue-specific immunity. Cell Res. 2020; 30:475-491. doi: 10.1038/s41422-020-0323-8.
  3. Moro K, Yamada T, Tanabe M, […], Ohtani M, Fujii H, Koyasu S. Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature. 2010; 463:540-544. doi: 10.1038/nature08636.
  4. Nussbaum JC, Van Dyken SJ, von Moltke J, […], Chawla A, Liang HE, Locksley RM. Type 2 innate lymphoid cells control eosinophil homeostasis. Nature. 2013; 502:245-248. doi: 10.1038/nature12526