TRACINg: T-Cell Reactivation by Antigen Presenting Cells In the Central Nervous System

• Applicant: Professor Dr. Ari Waisman
• Subject Area: Immunology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 446267576

Self-reactive T cells are central to the pathogenesis of autoimmune central nervous system (CNS) diseases, including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). To initiate an autoimmune response, antigen presenting cells (APCs) must reactive T cells within the CNS. Due to a lack of suitable tools, an unbiased analysis of the cell types that function as APCs in the CNS, and how different APCs can differentially affect T cells, has not been conducted. Addressing these questions will inform us on the underlying processes of CNS inflammation and will open new avenues for the development of targeted therapeutics for autoimmune disorders, such as MS.TRACINg will develop new, ground-breaking genetic tools to better understand the mechanism of CNS inflammation in the context of EAE and to answer the pertinent questions that current genetic models have thus far been unable to address.TRACINg is founded on two main aims: 1) to identify the specific APCs that reactivate T cells in the CNS at different stages of EAE, and 2) to trace labelled reactivated T cells after their interaction with defined APCs in the CNS to determine how APCs affect T-cell differentiation, migration and function.In Aim 1, we will use the LIPSTIC system to label, characterize and map the APCs that interact with antigen-specific T cells during reactivation in the CNS. In Aim 2, we will generate T cells that express Cre-recombinase upon antigen-specific triggering by specific APCs in the CNS. This approach will allow us to follow T cells as they migrate in and out of the CNS during neuroinflammation and to analyse the functional consequences of this interaction. These new genetic tools will not only advance neuroimmune research but will help to address the many open questions regarding the interactions between T cells and APCs in other T-cell-mediated diseases and immunological processes involving autoreactive T cells.

• DFG Programme: Reinhart Koselleck Projects