Abstract
The thymus is the site of T cell development in vertebrates. In general, the output of T cells is determined by the number of thymic epithelial cells (TECs) and their relative thymopoietic activity. Here, we show that the thymopoietic activity of TECs differs dramatically between individual mouse strains. Moreover, in males of some strains, TECs perform better on a per cell basis than their counterparts in females; in other strains, this situation is reversed. Genetic crosses indicate that TEC numbers and thymopoietic capacity are independently controlled. Long-term analysis of functional parameters of TECs after castration provides evidence that the number of Foxn1-expressing TECs directly correlates with thymopoietic activity. Our study highlights potential complications that can arise when comparing parameters of TEC biology across different genetic backgrounds; these could affect the interpretation of the outcomes of interventions aimed at modulating thymic activity in genetically diverse populations, such as humans.
Highlights
The thymus is the site of T cell development in all vertebrates[1]; the thymic rudiment emerges from the pharyngeal endoderm in close apposition with neural crest-derived mesenchyme and non-crest mesoderm[2], representing the primary lymphoid organ with the longest evolutionary history of spatial and functional conservation[3]
We examined whether the number of epithelial cells in the thymic microenvironment was correlated with thymus weight; thymus weight is largely determined by the number of haematopoietic cells which outnumber stromal cells by two to three orders of magnitude[2]
We found that the number of thymic epithelial cells (TECs) varies greatly between strains
Summary
The thymus is the site of T cell development in all vertebrates[1]; the thymic rudiment emerges from the pharyngeal endoderm in close apposition with neural crest-derived mesenchyme and non-crest mesoderm[2], representing the primary lymphoid organ with the longest evolutionary history of spatial and functional conservation[3]. With respect to the dynamics of the thymic epithelium, previous studies have indicated that the number of epithelial cells corresponds to the overall growth pattern of the thymus, with peak thymopoietic activity (expressed as the ratio of haematopoietic cells per thymic epithelial cells) at around 4 weeks of age[10]. No systematic analysis of potential strain-specific differences in TEC dynamics of male and female mice has yet been carried out This type of information is crucial, as strain- and sex-specific differences in TEC number and function directly impact the interpretation of phenotypes resulting from perturbations of thymus function. More than 100 years ago, it was noted that castration of male rodents resulted in significant changes in thymus mass[13] This observation has since been extended in numerous studies Our results provide clear evidence for strain- and sex-specific differences in thymus function; this complex interplay makes it difficult to interpret the outcome of therapeutic interventions aimed at improving thymus function in situations of immunodeficiency or during physiological age-related involution
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