Abstract
Progressive immune deficiency of aging is characterized by severe thymic atrophy, contracted T cell repertoire, and poor immune function. p63 is critical for the proliferative potential of embryonic and adult stem cells, as well as thymic epithelial cells (TECs). Because p63 null mice experience rapid post-natal lethality due to epidermal and limb morphogenesis defects, studies to define a role for p63 expression in TEC biology focused on embryonic thymus development and in vitro experiments. Since post-natal thymic stromal development and function differs from that of the embryo, we assessed the impact of lineage-restricted p63 loss on pre- and post-natal murine TEC function by generating mice with a loss of p63 function targeted to TEC, termed p63TECko mice. In adult p63TECko mice, severe thymic hypoplasia was observed with a lack in a discernable segregation into medullary and cortical compartments and peripheral T cell lymphopenia. This profound thymic defect was seen in both neonatal as well as embryonic p63TECko mice. In addition to TECs, p63 also plays in important role in the development of stratified epithelium of the skin; lack of p63 results in defects in skin epidermal stratification and differentiation. Interestingly, all adult p63TECko mice lacked hair follicles despite having normal p63 expression in the skin. Together our results show a critical role of TEC p63 in thymic development and maintenance and show that p63 expression is critical for hair follicle formation.
Highlights
The architectural organization and composition of the thymic epithelial cells (TECs) scaffold in cortex and medulla was assessed by immunohistology using anti-keratin antibodies directed at keratin (K)18 for cTECs and K5 for mTECs as well as reactivity to Ulex europaeus agglutinin 1 (UEA-1), a lectin that binds to mTECs [18]
Our data has shown that loss of p63 expression in TECs causes catastrophic loss of thymocytes
In post-natal mice, there was significant thymic hypoplasia in the thymocyte compartment in all subsets. These data indicate that p63 function is critical in TECs to ensure normal thymocyte differentiation
Summary
The thymus is essential for the growth, differentiation and selection of T cells whereby thymic epithelial cells (TECs), fibroblasts, B cells and hematopoietic cells constitute its major stromal. P63 conditional deletion in thymic epithelial cells controls thymus development and maintenance. Because mice germ-line deficient in p63 expression die early after birth, quantitative and qualitative studies concerning a role of p63 expression in TEC function and maintenance beyond the neonatal period were not possible [12]. To circumvent this limitation, we generated mice with a TEC-targeted loss of p63 expression to answer the question whether p63 expression is essential for postnatal TEC biology. We report here on the effects of p63 deletion in both the thymus and skin
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