Crosstalk between epithelial cells and intraepithelial lymphocytes at the intestinal barrier during infectious challenges

• Applicant: Dr. Christoph Drees
• Subject Area: Immunology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 410408922

Background: The gastrointestinal mucosa not only harbors a plethora of symbiotic microorganisms collectively referred to as the microbiota, it also exploits our immune system for tissue homeostasis and function. To build an efficient barrier between luminal contents and host tissue, intestinal epithelial cells (IEC) form a tight single cell layer and communicate with surveilling intraepithelial lymphocytes (IEL) for optimal host protection. The IEL pool is heterogeneous and contains a mixture of antigen-receptor bearing, tissue-resident lymphocytes and innate-like lymphoid cells, which however share similar characteristics of immune cell activation and effector function. Research Objective: How exactly IEC and IEL act independently and together to safeguard against intestinal infections however, is very incompletely understood. Even though genetic ablation of single IEL subsets had only moderate effects on combating infectious agents, there still might be non-redundant functions of single IEL subsets triggering a coordinated immune response for instance by the early secretion of pro-inflammatory cytokines attracting other IEL. Our goal is to decipher the cooperative network of intraepithelial immune cells and IEC necessary to combat infectious challenges. Methods: In this research project we are going to answer this question by infecting mice with different epitheliotropic pathogens (T. gondii, S. thyphimurium, Rotavirus) and investigating early events of IEL/IEC activation on a single cell level. Hence, we will utilize state of the art techniques and capture gene expression in single cells (scRNA-seq) by droplet-based microfluidics (Drop-seq) and protein expression by mass cytometry (CyTOF). Applying these models on mouse strains deficient for specific IEL subsets we will be able to clarify redundant and non-redundant properties of the heterogeneous IEL pool. In addition, we will also infect and analyze germ-free and gnotobiotic mice to investigate the role of the microbiota for IEL activation. While capturing the early IEC/IEL-mediated immune response at the intestinal barrier in its entirety we want to unveil distinct features of IEL hidden by a similar, innate-like mode of activation.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Albert Bendelac, Ph.D.