Population structure of myeloid cells in healthy and diseased human lungs.

• Applicants: Professorin Dr. Christine Falk; Professor Dr. Danny David Jonigk; Professor Dr. Joachim L. Schultze; Professor Dr. Gregor Warnecke; Dr. Bettina Wiegmann
• Subject Area: Immunology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 347286815

The lung is one of three organs that is directly exposed to pathogens and particles from the environment. Not surprisingly, the lung requires a local immune system that allows for fast and effective responses against such pathogens, yet secures organ integrity and function during any insult, infectious or non-infectious. Under homeostatic conditions, the lung harbors specialized immune cells including alveolar macrophages (AM), conventional and plasmacytoid dendritic cells (DCs), mast cells, innate lymphoid cells (ILCs), invariant natural killer T (iNKT) cells, NK cells, memory T cells, and regulatory T cells (Treg). Our understanding of immune cells has been greatly accelerated by classical phenotyping and functional analysis of cell surface marker defined immune cell populations. However, current phenotyping technologies used to distinguish subpopulations have also generated contradictory results. While a significant step forward, even technologies such as CyTof assessing 40 and more parameters are not designed to identify a subpopulation structure of immune cells in an entirely unbiased fashion. Particularly for the myeloid cell compartment in tissues such as the human lung, it is becoming increasingly difficult using classical approaches to unequivocally describe, understand and study the existing cellular heterogeneity and plasticity, not only in homeostasis, but particularly under pathological conditions.We hypothesize that we can gain a higher understanding of the true immune cell population structure of the human lung and the pathophysiology of the major diseases of the lung if we can assess the cellular compartments of the human lungs immune system, particularly the myeloid cell compartment at an unprecedented level of resolution (several hundred genes/per cell). We further hypothesize that such a high-resolution analysis is required to better understand the functionality of pulmonary immune system.With the advent of sequencing technologies on the single cell level (e.g. scRNA-seq), a completely new avenue has been opened and we are now in the position to apply such technologies to describe the true population structure of an organ of interest. Since technologies such as scRNA-seq have never been applied to immune cells in human healthy lung tissue and since we are in the fortunate position to combine our expertise in lung transplant biology, lung immune biology, macrophage biology, scRNA-seq, transcriptomics and bioinformatics, we propose to use scRNA-seq to discover the true population structure in the myeloid cell compartment of the human lung and to define the clinical impact of the new subpopulation structure for lung diseases and transplantation.

• DFG Programme: Research Grants