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In vitro generation of human T lymphocytes – from fetal thymic organ cultures (FTOC) to defined 3D culture systems

Prof. Thiel (first supervisor), Prof. Lendlein (second supervisor), Prof. Thiel (mentor); Charité

So far signals and mechanism of early T cell development have been mainly studied in murine experimental in vitro and in vivo systems employing gene targeting and/or transgenic mice. Whether and how these results hold true for human T cells or can be translated and used in clinical applications (e.g. T cell reconstitution) is not clear. We have established fetal thymic organ cultures (FTOC) in order to study directed in vitro differentiation of human thymic progenitor cells into mature human effector and regulatory T cells with defined specificities.
In this project we aim to characterize signals essential for human in vitro T cell development in the established FTOC system and translate this knowledge to set up in vitro human T cell development in defined threedimensional (3D) culture systems. We want to identify human thymic epithelial stem cells (TESC) in order to study in vitro differentiation of human medullary and cortical thymic epithelial cells (mTEC, cTEC) seeded in 3D bio-matrices. Finally culture systems shall be developed employing these 3D scaffolds and progenitor cells with differentiation potentials for mesenchym, TESC and hematopoietic cells such as T cells and dendritic cells. In vitro generated mature effector and regulatory T cells will be characterized for their function and specificities according to activation marker signatures described in our pre-work. A final long-term goal will be to establish human in vitro thymus generation to enable directed human in vitro T cell development, a particular challenge for regenerative cellular therapies.

Reference
Frentsch M, Arbach O, Kirchhoff D, Moewes B, Worm M, Rothe M, Scheffold A, Thiel A. 2005. Direct access to CD4+ T cells specific for defined antigens according to CD154 expression. Nat Med. 11: 1118-1124.