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Abstract

The thymus does not contain self-renewing T cell progenitors (TCP) and therefore requires continuous importation of progenitors from the blood to sustain T cell production. Recruitment of TCP to the thymus is facilitated by a multistep adhesion cascade initiated by the interaction of PSGL-1 expressed on TCP with P-selectin expressed on thymic endothelium. Thymic TCP importation is not a steady state process but is a periodic, gated event thought to be regulated by a negative feedback signal dependent on the occupation status of intrathymic TCP niches. However the nature of this feedback mechanism remains enigmatic. The aim of this study is to analyze the underlying mechanism that control thymic TCP importation in a temporal and quantitative manner. The study is based on the hypothesis that ingress of TCP into the thymus is controlled by the regulated expression of key molecules within the thymic adhesion cascade. Indeed, the first set of data shows that Pselectin and CCL25 expression correlate with thymic receptivity. Furthermore, this study finds that P-selectin and CCL25 are periodically expressed in thymic tissues indicating that they are essential parts of the thymic gate-keeping-mechanism. Absence of the P-selectin on thymic endothelial cells or functional P-selectin ligands on TCP significantly reduces the numbers of the earliest intrathymic TCP population and abolishes periodic expression of Pselectin and CCL25 suggesting that niche occupancy plays a role in regulating the periodicity of thymic TCP importation. The study further shows that the size of the peripheral lymphocyte pool directly affects thymic P-selectin expression and TCP receptivity indicating that extrathymic factors also control thymic receptivity. As a feedback signal that could mediate changes in the peripheral lymphocyte pool into altered thymic TCP receptivity sphingosine-1-phosphate (S1P) was identified. These findings suggest a model whereby thymic TCP importation is controlled by both early thymic niche occupancy and the peripheral lymphocyte pool via S1P.