http://repub.eur.nl/res/aut/49869/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/34917/ 2012-01-01T00:00:00Z In wild-type mice, T-cell receptor (TCR) γδ+cells differentiate along a CD4 CD8 double-negative (DN) pathway whereas TCRαΒ+cells differentiate along the double-positive (DP) pathway. In the human postnatal thymus (PNT), DN, DP and single-positive (SP) TCRγδ+populations are present. Here, the precursor-progeny relationship of the various PNT TCRγδ+populations was studied and the role of the DP TCRγδ+population during T-cell differentiation was elucidated. We demonstrate that human TCRγδ+cells differentiate along two pathways downstream from an immature CD1+DN TCRγδ+precursor: a Notch-independent DN pathway generating mature DN and CD8αα SP TCRγδ+cells, and a Notch-dependent, highly proliferative DP pathway generating immature CD4 SP and subsequently DP TCRγδ+populations. DP TCRγδ+cells are actively rearranging the TCRα locus, and differentiate to TCR DP cells, to CD8αΒ SP TCRγδ+cells and to TCRαΒ+cells. Finally, we show that the γδ+subset of T-cell acute lymphoblastic leukemias (T-ALL) consists mainly of CD4 SP or DP phenotypes carrying significantly more activating Notch mutations than DN T-ALL. The latter suggests that activating Notch mutations in TCRγδ+thymocytes induce proliferation and differentiation along the DP pathway in vivo. http://repub.eur.nl/res/pub/33369/ 2011-07-02T00:00:00Z Progressive loss of renal function is associated with a dysregulation of circulating T cells that may underlie their impaired T-cell immunity. Here we tested whether end-stage renal disease (ESRD)-related T-cell alterations are compatible with the concept of premature immunological aging. Younger patients (25-45 years old) with ESRD were found to resemble older healthy controls (60-80 years old) as they had a significant loss of naive T cells and a relative increase of memory T cells showing progressive terminal differentiation. A significant decrease in the content of T-cell receptor excision circles and telomere length in patients with ESRD confirmed these phenotypic data. The loss of naive T cells in patients with ESRD was associated with an excessive age-related decrease of recent thymic emigrants, indicating a premature decline in thymic function. Additionally, increased homeostatic proliferation of naive T cells was found in patients with ESRD, similar to that of older healthy individuals, with an increased susceptibility for activation-induced apoptosis. Therefore, both decreased thymic output and increased susceptibility of naive T cells for apoptosis may play a role in the loss of naive T cells in ESRD patients. Thus, our results are compatible with premature aging of the T-cell system of patients with ESRD comparable with that of healthy individuals 20-30 years older.