Thymic selection of MAIT cells

• Applicant: Professor Dr. Andreas Krueger
• Subject Area: Immunology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432290466

T cells constitute a central part of the adaptive immune system. In addition, certain T cell populations, frequently referred to as unconventional T cells, exist that share functional profiles of both, innate and adaptive immunity. Mucosal-associated Invariant T (MAIT) cells are part of this group of T cells. They constitute a very abundant population in various human tissues, comprising almost 10% of all blood T cells and 20-40% of all liver T cells. MAIT cells express a semi-variant T cell receptor (TCR) and recognize vitamin B metabolites. In keeping with their innate-like nature they are also able to directly respond to stimulation by cytokines. In contrast to humans, MAIT cells are exceedingly rare in mice. Therefore, the understanding of MAIT cell function and, even more so, their development, remain in its infancy. MAIT cells share some characteristics with invariant natural killer T cells, but some notable differences exist as well. Our laboratory has recently demonstrated that MAIT cell development critically depends on a single miRNA, miR-181a/b-1. Here, we propose to study MAIT cell development to answer fundamental open questions: 1) Do MAIT cells, like other unconventional T cells, depend on strong TCR signals during development? 2) What are the metabolic requirements of MAIT cells during development in the thymus? 3) What additional molecular mechanisms, such as survival signals, are key to MAIT cell development in the thymus? To address these questions, we will take advantage of genetic tools including a molecular timer revealing a cell’s developmental age as well as a recently generated mouse strain with increased abundance of MAIT cells. Together, the experiments proposed will substantially add to our understanding of the molecular mechanisms underlying MAIT cell generation in the thymus. These studies will therefore foster our understanding of MAIT cell biology in general and may help to better understand the role of MAIT cells during an immune response.

• DFG Programme: Research Grants