Open Research Projects, Research

Dissecting the role of ILC2-derived IL-5 for eosinophil development and homeostasis

Prinicipal Investigator

Dr. Christoph Klose
Dr.Claudia Dürr

Scientific interest within the context of the graduate college:

Tissue homeostatic functions of innate lymphoid cells
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 stimuli1. 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 activated3, 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 (Nmur1Cre). Using this model, we could recently show that ILC2s are the major determinant of eosinophil homeostasis in tissues if ILC2 are genetically ablated.4,5 Since the phenotype of these mice closely reassembled the deficiency in eosinophils reported in IL-5 knockout mice6, and ILC2s were shown to be a major producer of IL-5 tissues7, we hypothesize that ILC2-derived interleukin 5 is indispensable for eosinophil development and function. To this end, we crossed Nmur1Cre and Il5fl/fl mice to conditionally delete of IL-5 in ILC2s, which brings us in the position experimentally test our hypothesis. In Aim 1 of the project, eosinophil development will be monitored in detail using mainly multicolor flow cytometry. In Aim 2, we will investigate the effects of ILC2-derived IL-5 on tissue homeostasis and allergic lung inflammation in our conditional knockout mice. 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. Jarick KJ, Topczewska PM, Jakob MO, […], Diefenbach A, Artis D, Klose CSN. Non-redundant functions of group 2 innate lymphoid cells. Nature. 2022; 611:794-800, doi:10.1038/s41586-022-05395-5.
  5. Topczewska PM, Rompe ZA, Jakob MO, […], Kotsch K, Artis D, Klose CSN. ILC2 require cell-intrinsic ST2 signals to promote type 2 immune responses. Front Immunol. 2023; 14:1130933. doi: 10.3389/fimmu.2023.1130933.
  6. Kopf M, Brombacher F, Hodgkin PD, […], Köhler G, Young IG, Matthai KI. IL-5-deficient mice have a developmental defect in CD5+ B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses. Immunity. 1996; 4:15-24, doi: 10.1016/s1074-7613(00)80294-0.
  7. 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.