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Stromal Cell Niches at the Nexus of the Innate Lymphoid Cell Interactome

Burkhard Ludewig & Mechthild Lütge

abstract Innate lymphoid cells (ILCs) critically impact a diverse array of diseases. While the main cell-intrinsic molecular pathways and some of the soluble mediators that regulate ILC development and their functional activity have been characterized, the cell-extrinsic microenvironments that determine where, when and how ILCs are maintained and their activity is controlled, have remained largely unknown. Since ILCs contribute to numerous inflammatory diseases, these gaps in our knowledge ultimately limit our ability to therapeutically target critical pathways that influence ILC function. Based on our published and unpublished data, we hypothesize that (i) particular FRC subsets generate essential niches for ILC maintenance and differentiation within SLOs, and that (ii) distinct molecular interactions between FRCs and ILCs determine activation and regulation of ILC subsets and thereby determine the outcome of immune reactions.
The overarching goal of this project is to decipher the functional atlas of fibroblastic reticular cell (FRC)-dependent ILC niches through the combination of state-of-the-art models for in vivo FRC targeting and novel methods from quantitative systems biology. Moreover, molecular perturbation analysis of FRC-ILC niches will validate the importance of such dual-sided interactions during infection. The main goal of Aim 1 is to reveal the molecular signature of active cellular processes during FRC-ILC interaction. To this end, we will implement and exploit advanced mass spectrometry-based imaging of murine lymphoid tissues. Moreover, we will use latest single cell RNA-seq technology to analyze the transcriptome and signaling pathways involved in FRC-ILC interaction. In Aim 2, novel mouse models will be utilized to molecularly perturb FRC-ILC interaction and to determine to what extent these niches are critical for the initiation and regulation of immune responses against infections with viruses, bacteria or parasites. The work on Aim 3 will deliver inducible FRC targeting models for the analysis of FRC subsets and will unveil whether and how FRC subset-dependent niches impact immune responsiveness during infection.
The stringent focus of the research program on stromal cells as central hubs for the control of ILC development and differentiation will reveal novel principles underlying immune homeostasis and immunity against infections, hence shifting general paradigms of immune regulation. Moreover, the implementation of mass spectometry-based imaging in combination with powerful mouse genetics will unfold the functional atlas of FRC-ILC niches to guide strategies for ILC- and stromal cell-targeting therapies.
   
project partner Dr. Mark Robinson, Institut of Molecular Life Sciences Universität Zürich
Prof. Bernd Bodenmiller, Universität Zürich
type of project fundamental research
status ongoing - recruiting phase
start of project 2019
end of project 2022
project manager Prof. Burkhard Ludewig