Mathematical modeling of T cell differentiation from hemopoietic stem cell progenitors

The process of T cell differentiation from hemopoietic stem cell (HSC) progenitors occurs within the thymic microenvironment. During thymocyte development, tolerance to self is established by elimination of autoreactive T lymphocytes expressing T cell receptors (TCR) with high affinity to self-peptides in the process of negative selection. In contrast, positive selection generates functionally and phenotypically mature T cells which recognize foreign antigens following egress from the thymus into the peripheral T cell pool. In recent years there have been advances in the understanding of molecular and cellular pathways controlling thymocyte differentiation, often regarded by experimental biologists as unidirectional and synchronous processes, in which cells spend a fixed time at each successive developmental stage. However, mathematical modeling has suggested that differentiating cell systems are more complex than previously believed. For example, non-linear transitions and feedback effects have been shown in our models for T cell development and their receptor repertoires. In this review, we discuss the feedback regulation of HSC differentiation by mature T cell subsets as revealed by mathematical modeling, in an attempt to understand how the repertoires of these cells are generated and regulated.