Our immune system has evolved sophisticated strategies to achieve protective immunity. While immune reactions are critical to combat pathogens and maintain tissue homeostasis, its deregulation leads to tissue damage or even inflammatory and autoimmune diseases. The high system complexity of the interplay of multiple cell-types each with their own function, however, impedes analysis and interpretation of immune function in health and disease.

The research of our group aims at understanding questions of broad relevance to various fields in which immune reactions play significant roles. We focus on

Link1) how molecular sensing of self and foreign signals intracellularly and

Link2) how intercellular signaling orchestrates context dependent immune reactions and confers protection against disease.

Whenever possible, we work with primary human or mouse cells with a focus on cell types with key roles in orchestrating immune reactions including monocytes, macrophages, and dendritic cells.

We address these questions systems-wide on the level of proteins, which are key in transmitting intra- and intercellular signals, by employing a unique combination of experimental immunology, biochemistry, mass spectrometry based proteomics, and systems biology:

(i) We develop and apply biochemical and proteomics discovery tools for the unbiased characterization of immune functions.
(ii) We employ bioinformatics strategies to obtain a holistic view on host defense and to discover proteins or protein modifications with key signaling roles.
(iii) We generate testable hypothesis and investigate the function and molecular mechanisms of the discovered leads with a range of cellular, molecular, biochemical, biophysical as well as immunological methods.

Our laboratory is embedded in the Department of Proteomics and Signal Transduction generating a unique infrastructure, in which we share proteomics and computational technologies with Matthias Mann’s and Juergen Cox’s group. We believe that scientific progress can be achieved best by collaborative research across disciplines and we have established a network of national and international collaborators to translate our tools and findings into biologically important areas.

1) Intracellular signaling:

Pattern recognition receptors (PRRs) are germ-line encoded sensors of microbial or danger associated molecular entities. Chemical alterations, dislocations or phase transitions of host molecules trigger immune responses comparable to microbial structures and therefore make PRRs and their downstream signaling pathways important not only for host protection against pathogens, but also for sterile inflammatory conditions in e.g., rheumatoid arthritis, gout and neurodegeneration as well as metabolic diseases such as atherosclerosis, type 2 diabetes and many others. PRR signal initiation and integration, which function mainly by protein interactions, translocations or modifications to allow fast and efficient intracellular signal transduction, however, is incompletely characterized.

To unravel how signaling through PRRs elicit tailored immune responses, we have developed a proteomics discovery toolbox to identify novel and post-translational modifications (PTMs), protein-protein interactions and protein translocations that control PRR signaling and protective immunity. By combining unbiased interaction and PTM proteomics, we have discovered novel and dynamic protein interactions as well as posttranslational modifications in selected Toll- and Nod-like receptor (TLRs/NLRs) signaling cascades. We validated the functional relevance of identified regulations by streamlined loss or gain of function experiments based on a CRISPR/Cas9 knockout or introduction of mutations of the covalently modified sites, respectively. Currently, we are investigating the molecular mechanisms of selected leads in detail. In the future, we aim to deduce the general principles for the cooperative interplay of intracellular signal transduction mechanisms and elucidate strategies to perturb intracellular signaling to manipulate immune responses.

2) Intercellular signaling:

Distinct immune functions are executed by highly specialized cell types. However, the architecture and syntax by which biological messages, such as cytokines with pleiotropic functions, are exchanged to enable protection against disease is a central feature of the immune system that remains incompletely understood. Moreover, the functions of transmitted messages vary depending on the cellular sender, receiver and pathophysiological state, making the interpretation of immune responses inherently challenging.

To unravel the complex interplay between different cell types, we have recently invented two milestone proteomics approaches: First, we have developed a discovery-driven method for the sensitive detection of secreted proteins (Meissner et al. 2013, see Publications). This allows us to quantify proteins secreted from rare primary cell populations and identify routinely up to 50 annotated cytokines as well as secreted proteins with yet unknown extracellular functions. Second, we established an experimental and computational framework to construct comprehensive intercellular signaling networks based on ligand-receptor and receptor-receptor interactions (Rieckmann et al. 2017, see Publications). This allows us to identify physiologic cell-to-cell communication structures between various cell types as well as its alterations during pathology.

The application of our secretomics technology on cells with prominent roles in orchestrating immune reactions lead to the discovery of cellular subsets with distinct intercellular functions as well as proteins with unexpected extracellular roles. Our studies revealed cytokine-like activity for some of these proteins, suggesting a general underestimation of auto- and paracrine protein functions. We are currently characterizing the physiology of these proteins, their corresponding receptors and cell-type specific expression patterns.

While our studies focused primarily on circulating immune cells, we are now moving towards investigating the context dependent crosstalk at the interfaces of immune cells with non-immune cells, microbes and eventually even in complex organs. In the future, we aim to decipher the contribution of intercellular signals to different inflammatory pathologies and to develop strategies to interfere with aberrant intercellular communication. 


Interested in joining our team? Check out our LinkOpen Positions.

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