Prof JC Zuniger Pflucker
- Lymphocyte differentiation
- T cell development
- Thymus biology
- Notch signaling
The process of differentiation within the immune system allows a small population of continuously self-renewing stem cells to generate a remarkably diverse range of mature progeny. Understanding how molecular signals in developing tissues induce commitment and differentiation of stem cells is a fundamental question of developmental biology. In the context of blood cells, this question also has therapeutic implications in the treatment of leukemia, which arises from dysregulated differentiation.
In the context of the immune system, the thymus provides a model system to study the mechanisms controlling tissue-specific differentiation events and lineage commitment pathways. Hematopoietic progenitor cells from the bone marrow migrate to the thymus where they receive the necessary signals that mediate their commitment and differentiation into T lymphocytes. The absolute requirement for the thymus in the generation of T cells from hematopoietic progenitors has been recognized for over 50 years. However, the precise molecular interactions responsible for this thymic requirement remained elusive.
We contributed to the identification of these molecular interactions by demonstrating that a bone marrow-derived stromal cell line (OP9) ectopically expressing Delta-like-1 (OP9-DL1), a Notch receptor ligand, gains the ability to induce the full differentiation of T cells from hematopoietic stem cells (HSC). Interestingly, expression of Delta-like-1 or Delta-like-4 by OP9 cells results in a complete switch in lymphocyte lineage commitment, as control OP9 cells allow for robust B cell differentiation, while OP9-DL cells support only T cell differentiation from HSCs.
We extended these findings by showing that totipotent embryonic stem cells (ESCs) can also be induced to differentiate into functional T cells in vitro by coculture on OP9-DL cells. Thus, our findings show that Delta-like/Notch interactions occurring within the thymus underpin its unique ability to induce the lineage commitment and differentiation of T cells. With this in mind, our focus is on identifying the molecular mechanisms that govern progenitor lymphocyte lineage commitment, T cell development, and Delta-like-4 expression by thymic stromal cells, and the development of a stromal cell-free system for the induction of T cell differentiation from defined sources of stem cells. We are also developing strategies to adapt our current model system for the induction of T cell differentiation from defined sources of human stem cells. One important potential application of our work will be the directed generation of human progenitors T cells to facilitate immune regeneration of T cells.