2025-06-23 ミュンヘン大学(LMU)
<関連情報>
- https://www.lmu.de/en/newsroom/news-overview/news/biophysics-function-of-thymus-gives-rise-to-form.html
- https://www.pnas.org/doi/10.1073/pnas.2415288122
胸腺機能を担う基本的相互作用が凸状髄質の形状を説明する Basic interactions responsible for thymus function explain the convoluted medulla shape
David Muramatsu, Henrik Weyer, Florian M. Gartner, and Erwin Frey
Proceedings of the National Academy of Sciences Published:June 20, 2025
DOI:https://doi.org/10.1073/pnas.2415288122
Significance
The thymus organ produces and selects nascent T cells (thymocytes) to establish a competent T cell repertoire, which is a central component of the adaptive immune system. Thymocyte production and (negative) selection occur in two spatially segregated tissues, the cortex and medulla, which in mice are intertwined in a convoluted spatial structure. By modeling the central, experimentally verified cell–cell signaling pathways, we show that the cross-talk between negatively selected thymocytes and medullary-tissue cells enables the mouse thymus to self-organize into its complex internal architecture. The cross-talk acts as a feedback which ensures the robust organization of a spatial structure that allows the efficient negative selection of thymocytes. In that sense, in the model, form follows function because function elicits form.
Abstract
The thymus is one of the most important organs of the immune system. It is responsible for both the production of T cells and the prevention of their autoimmunity. It comprises two types of tissue: The cortex, where nascent T cells (thymocytes) are generated; and the medulla, embedded within the cortex, where autoreactive thymocytes are eliminated through negative selection. In mice, the medulla exhibits a complex, convoluted morphology, which has raised the question of whether its form impacts its function. Intriguingly, experiments also reveal a reverse dependency: The interactions between medullary stroma and thymocytes shape the medullary structure. However, an understanding of the underlying mechanisms of medulla morphogenesis emerging from these interactions remains elusive. Here, we present a conceptual theoretical model showing that central, experimentally verified signaling pathways suffice to shape the convoluted medullary structure. The mathematical analysis of the model explains the observed effects of chemotaxis on thymocyte localization, and the reported morphological changes resulting from the modulation of thymocyte production. Our findings reveal that the cross-talk between medulla growth and negative selection of thymocytes not only regulates medullary volume but also orchestrates the morphology of the thymus medulla. This mechanism of structure formation robustly organizes the medulla in a way that accelerates thymocyte negative selection by improving their chemotactic migration into the medulla. Thereby, we identify a feedback between the function of the thymus medulla and its form. Our theoretical study motivates further experimental analysis of the spatial distribution of thymic cell populations and predicts morphological changes under genetic perturbations.
