The role of ILC3 in autoimmune inflammation

• Applicant: Professor Dr. Ari Waisman
• Subject Area: Immunology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320374141

Cells that are regulated by the transcription factor ROR gamma (g)t have critical functions in immunity but also can play a harmful role in autoimmune processes. These cells produce the pro-inflammatory cytokines IL-17 and IL-22, which are important not only to maintain the barrier integrity of mucosal surfaces, but can also promote uncontrolled inflammation and contribute to tissue damage. There are four major groups of cells that can express RORgt-dependent IL-17, including on the one hand the adaptive RAG-dependent alpha-beta T cells (Th17 and Tc17) and gamma-delta T cells and on the other hand the group 3 innate lymphoid cells (ILCs), comprising LTi cells and ILC3s. In order to express RORgt most T cells need to be activated by exposure to environmental factors, such as the microbiota. In sharp contrast, group 3 ILCs are characterized by a constitutively active RORgt transcriptional profile, including the expression of IL-22 and to a lower extent IL-17, both being critical in the early responses to infections and tissue injury. Recently, it was shown that ILC3s can express MHC class II molecules, making them potential antigen presenting cells (APCs), a unique feature for lymphoid cells in the mouse. In contrast to other APCs, ILC3s interaction with CD4 T cells, via MHC class II was shown to induce tolerance rather than immunity, therefore suggesting that ILC3s may contribute to novel mechanisms of peripheral tolerance. In the frame of this grant application we plan to study the role of ILC3s as either promoters or suppressors of inflammatory processes, in steady state and pathology, using novel genetic tools generated especially for this project. Furthermore, we will engineer a new system that will allow us to specifically ablate ILC3s to study homeostatic T cell responses as well as autoimmunity in their absence. In addition, we will use conditional gene targeting to either remove MHC class II from ILC3s or force these cells to specifically present an autoantigen. We will then use these mice to study whether antigen presentation by ILC3s results in tolerance of autoreactive T cells in vivo. Finally, we plan to use unique genetic tools to investigate how IL-1 and IL-6 signaling, respectively, affects the development, plasticity and function of ILC3s. Our studies should help to better understand the biology of this rather new cellular player of innate immunity, specifically tackling the role played by ILC3s in inflammation and autoimmunity.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1937: Innate Lymphoid Cells
• Co-Investigator: Dr. Tommy Regen