Abstract
Intrathymic T cell development is an important process necessary for the normal formation of cell-mediated immune responses. Importantly, such a process depends on interactions of developing thymocytes with cellular and extracellular elements of the thymic microenvironment. Additionally, it includes a series of oriented and tunely regulated migration events, ultimately allowing mature cells to cross endothelial barriers and leave the organ. Herein we built a cellular automata-based mathematical model for thymocyte migration and development. The rules comprised in this model take into account the main stages of thymocyte development, two-dimensional sections of the normal thymic microenvironmental network, as well as the chemokines involved in intrathymic cell migration. Parameters of our computer simulations with further adjusted to results derived from previous experimental data using sub-lethally irradiated mice, in which thymus recovery can be evaluated. The model fitted with the increasing numbers of each CD4/CD8-defined thymocyte subset. It was further validated since it fitted with the times of permanence experimentally ascertained in each CD4/CD8-defined differentiation stage. Importantly, correlations using the whole mean volume of young normal adult mice revealed that the numbers of cells generated in silico with the mathematical model fall within the range of total thymocyte numbers seen in these animals. Furthermore, simulations made with a human thymic epithelial network using the same mathematical model generated similar profiles for temporal evolution of thymocyte developmental stages. Lastly, we provided in silico evidence that the thymus architecture is important in the thymocyte development, since changes in the epithelial network result in different theoretical profiles for T cell development/migration. This model likely can be used to predict thymocyte evolution following therapeutic strategies designed for recovery of the thymus in diseases coursing with thymus involution, such as some primary immunodeficiencies, acute infections, and malnutrition.
Highlights
T lymphocytes play an important role in the adaptive immune response and their development is fundamental in the process of defense against pathogens as well as tumor cells
The values were determined by adjusting the pre-designed model to the experimental results previously obtained with mice, in which thymocyte development was evaluated during thymus recovery following sub-lethal c-ray irradiation [24]
The mathematical model developed for thymocyte migration and differentiation is in agreement with experiments that evaluated thymus repopulation from double-negative cells, following sub-lethal irradiation in mice [24]
Summary
T lymphocytes play an important role in the adaptive immune response and their development is fundamental in the process of defense against pathogens as well as tumor cells. Migration through the thymic lobule is crucial for thymocyte development, and is influenced by chemokines and by interactions with a network of microenvironmental cells, whose major component is the epithelium [2,3,4] This migratory process occurs in a spatially and chronologically well-defined manner that can be summarized as follows: 1) the entry of bone marrow-derived double negative (DN) (CD42CD82) progenitors into the thymus by cortex-medulla junction (CMJ); 2) migration of immature DN cells, from the CMJ towards the subcapsular zone (SCZ) of the thymic lobule, with subsequent proliferation and differentiation of double positive (DP) (CD4+CD8+) cells; 3) reorientation of the migratory process, towards the medulla, positive selection, and generation of single positive (SP, CD4+CD82 or CD42CD8+) cells; 4) further interactions of SP thymocytes with epithelial and dendritic cells in the medulla for complete development (negative selection) to ensure central tolerance; and 5) egress of mature SP T cells to peripheral lymphoid organs
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