PDGFRα-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches

Abstract

The thymus provides a specialized site for the production of T cells capable of recognizing foreign antigens in the context of self-major histocompatibility complex (MHC) molecules. During development, the thymus arises from an epithelial rudiment containing bipotent progenitors that differentiate into distinct cortical and medullary epithelial cells to regulate the maturation and selection of self-tolerant CD4+ and CD8+ T cells. In addition to their differentiation, thymic epithelial cells undergo cellular expansion to ensure that sufficient intrathymic cellular niches are available to support the large number of immature thymocytes required to form a self-tolerant T-cell pool. Thus, intrathymic T-cell production is intimately linked to the formation and availability of niches within thymic microenvironments. Here, we show the increase in intrathymic niches caused by the proliferation of the epithelium in the developing thymus is temporally regulated, and correlates with the presence of a population of fetal thymic mesenchyme defined by platelet-derived growth factor receptor alpha (PDGFRalpha) expression. Depletion of PDGFRalpha+ mesenchyme from embryonic thymi prior to their transplantation to ectopic sites results in the formation of functional yet hypoplastic thymic tissue. In summary, we highlight a specialized role for PDGFRalpha+ fetal mesenchyme in the thymus by determining availability of thymic niches through the regulation of thymic epithelial proliferation.

Redefining epithelial progenitor potential in the developing thymus

“…This discrepancy may reflect differences in efficiency for thymus formation or proliferative potential between Mts24 + and Mts24 -cells at this stage that are only evident when very small numbers of cells are grafted. However, our observation that matched numbers of Mts24 + and Mts24 -gave rise to grafts of similar size and are able to support the generation of similar numbers of thymocytes, implying the presence of similar numbers of epithelial cells which are known to be limiting for thymocyte production [26], argues against any difference in proliferative potential or longevity in these populations.…”

Generation of Thymic Epithelial Cell Progenitors by Mouse Embryonic Stem Cells

“…Such defects have dramatic effects on intrathymic T-cell development, leading to severe immunodeficiency [1][2][3]. Restriction of the number of thymic epithelial cells has been shown to result in a reduced number of T cells in the thymus [4][5][6]. This, along with changing TEC function, is believed to be one of the major factors in age-dependent thymic involution [2].…”

Thymic Mesenchymal Cells Have a Distinct Transcriptomic Profile

“…This is notably the case for thymic MCs. During development, thymic MCs regulate the proliferation of thymic epithelial cells through production of fibroblast growth factor (FGF)-7 and -10, insulin-like growth factor (IGF)-1 and -2, and retinoic acid (7)(8)(9)(10)(11). However, little is known of the role of thymic MCs during postnatal life, aside from the fact that CD248 + MCs play a role in revascularizing thymuses during infectiondependent regeneration and that FSP1 + MCs are essential for the maintenance of the medullary thymic epithelium (12,13).…”