Real-time quantitative in vivo imaging of chemokine and chemokine receptors dynamics during intrathymic cell migration

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Cell migration is essential for T cell development in the thymus. Thymocytes use chemokine and chemokine receptors to migrate in and out of distinct thymic microenvironments to interact with other cells and receive signals for their differentiation into T cells. Alteration of cell migration can results in either defective T cell development or autoimmunity. Our current understanding how thymocytes control their migration derives from studies of cultured cells or analysis on fixed tissue sections. It is unclear how thymocytes control their migratory behavior within the thymus, where they encounter multiple chemical cues from various sources. We have recently established a new system to directly study T cell development at whole organ level. The outcomes of our in vivo imaging approach have provided valuable insights into the migration behavior of all thymocytes in a full functional thymus: Thymocytes show an overall heterogeneous migratory behavior, lacking a discernable global pattern. However, thymocytes at the same developmental stage exhibit characteristic migratory pattern. In this interdisciplinary project, we will address fundamental questions regarding how do thymocytes sense and respond to distinct thymic microenvironments and how is T cell differentiation linked to cell interaction and migration behavior. We take advantages of a unique combination of quantitative in vivo imaging and cutting edge molecular tools, which we have developed, to measure the activity of chemokine and chemokine receptors in real-time. High-content imaging data will provide the rich spatiotemporal resolution that is needed to develop mathematical models to fully understand how cell dynamics is regulated in the thymus. In addition, we will characterize the molecular mechanisms regulating the expression of chemokine receptors at the transcriptional and post-translations levels. The outcomes obtained from the in vivo system will gain insight into the dynamic aspects of T cell development, which will be of relevance to the human system.