Thymic selection of MAIT cells
Final Report Abstract
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. In order to identify potential underlying molecular mechanisms, we first identified target structures of miR-181-a/b-1 in thymocytes. This approach not only substantially expanded the spectrum of physiologically relevant targets of miR-181a/b-1, but also resulted in the identification of alternative mechanisms of miRNA-mediated gene repression for defined target groups. Second, we demonstrated that miR-181-a/b-1 in the thymus not only controls development of unconventional T cells, but also substantially influences the selection of conventional T cells. Of note, miR-181a/b-1 regulates both positive selection of T cells by modulating cell death regulators and negative selection by controlling signal transduction through the TCR. Finally, in this project we characterized metabolic changes in the context of MAIT cell selection in the thymus and in the periphery dependent on different stimulation conditions. While conventional T cells undergo a qualitative switch to glucose as their primary energy source upon stimulation, we discovered that MAIT cells increase their metabolic activity after stimulation by increased utilization of multiple energy sources. In summary, this project provided in depth insight into miRNA biology in the context of T-cell biology and beyond, and fostered our understanding of metabolic control of MAIT cell function.
Publications
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MicroRNA miR-181—A Rheostat for TCR Signaling in Thymic Selection and Peripheral T-Cell Function. International Journal of Molecular Sciences, 21(17), 6200.
Grewers, Zoe & Krueger, Andreas
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Post-transcriptional control of T-cell development in the thymus. Immunology Letters, 247, 1-12.
Krueger, Andreas; Łyszkiewicz, Marcin & Heissmeyer, Vigo
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A high-resolution map of functional miR-181 response elements in the thymus reveals the role of coding sequence targeting and an alternative seed match. Nucleic Acids Research, 52(14), 8515-8533.
Verheyden, Nikita A.; Klostermann, Melina; Brüggemann, Mirko; Steede, Hanna M.; Scholz, Anica; Amr, Shady; Lichtenthaeler, Chiara; Münch, Christian; Schmid, Tobias; Zarnack, Kathi & Krueger, Andreas
