Homeostasis of T cells is essential to the maintenance of the T cell pool and TCR diversity. In this study, mechanisms involved in the regulation of cytokine-mediated expansion of naive T cells in the absence of Ag, in particular the role of caspase activation and susceptibility to apoptosis of recent thymic emigrants (RTEs), were examined. Low level caspase-8 and caspase-3 activation was detected in proliferating IL-7-treated cells in the absence of cell death during the first days of culture. Caspase inhibitors suppressed IL-7-induced expansion of RTEs. Low level expression of CD95 and blocking Ab experiments indicated that this early caspase activation was CD95 independent. However, CD95 levels subsequently became dramatically up-regulated on proliferating naive T cells, and these cells became susceptible to CD95 ligation, resulting in high level caspase activation and apoptotic cell death. These results show a dual role for caspases in proliferation and in CD95-induced cell death during Ag-independent expansion of RTEs. This method of cell death in IL-7-expanded RTEs is a previously unrecognized mechanism for the homeostatic control of expanded T cells.

Cord blood (CB) cells are now an important source of stem cells for bone marrow reconstitution as a result of the decreased risk of graft-versus-host disease that was attributed to previously reported absent or diminished nuclear factor of activated T (NFAT) cell 1 expression by CB T cells. This study reexamines NFAT1 expression in CB T cells. CB T cells were examined for NFAT1 mRNA and protein expression. These cells were then stimulated, and NFAT1 translocation and interleukin-2 production were assessed. Our results show that resting CB CD4+ T cells express NFAT1 mRNA and protein at levels similar to their adult counterparts. On stimulation, NFAT1 is translocated into the nucleus where DNA binding can occur, whereas calcineurin inhibition prevents interleukin-2 production. We conclude that differential responsiveness of CB T cells cannot be attributed to differences at the level of NFAT1 expression or its ability to function in these cells but may represent an altered sensitivity to stimulation.