Thymus and T cell development in the mouse
The thymus is a primary lymphoid organ whose function is to provide mature and self-tolerant T lymphocytes that are required to fight infection and maintain tissue integrity. Thymopoiesis depends on the provision of a dedicated epithelial microenvironment that attracts, maintains and specifies T cell progenitors and supports their differentiation into mature, self-tolerant T cells. We are interested in the molecular basis of thymic epithelial development and the characterization of the epithelial progenitor cell, and are studying the molecular mechanisms of TEC specifica- tion, proliferation and differentiation.
We have previously shown that the function of the stromal niche required for the attraction and specification of lymphoid progenitor cells depends on the Foxn1 transcription factor. We have rebuilt this niche function in vivo in transgenic mice nullizygous for Foxn1 by re-expression of individual target genes of the Foxn1 transcription factor, singly or in combination. To date, we have achieved the reconstitution of T cell development until the CD4+CD8+-double-positive stage of developing thymocytes using just two factors, Cxcl12 and Dll4. Ultimately, we wish to use this information to engineer artificial thymus stroma at ectopic sites as a potential means of countering the ill-effects of diseased thymic tissue.
We are also interested in examining the molecular basis of thymus involution, a physiological process that leads to reduced output of naïve T cells in ageing individuals.