IL-7-Regulated Homeostatic Maintenance of Recent Thymic Emigrants in Association with Caspase-Mediated Cell Proliferation and Apoptotic Cell Death

Abstract

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.

Carbon Monoxide Inhibits T Lymphocyte Proliferation via Caspase-Dependent Pathway

“…We also demonstrated that the antiproliferative effect of CO in airway smooth muscle cells is mediated by the extracellular signal-regulated kinase MAPK pathway (13). Most of the biological effects attributed to CO including anti-inflammatory, antiapoptotic, and now antiproliferative effects have been linked to its ability to modulate the activity of guanylate cyclase and to increase the levels of cellular cGMP (7,14,25,26,28,33,34) and/or the MAPK pathways such as p38 or extracellular signalregulated kinase.…”

“…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 (34). Caspase inhibitors suppressed IL-7-induced expansion of recent thymic emigrants (34).…”

“…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 (34). Caspase inhibitors suppressed IL-7-induced expansion of recent thymic emigrants (34). The caspase-8 inhibitor c-FLIP L modulates TCR-induced proliferation but not activation-induced cell death of lymphocytes (35).…”

Homeostasis of the Naive CD4+ T Cell Compartment during Aging

“…Peripheral expansion can be evidenced by the large reduction in TREC content in the naive CD4 ϩ T cell pool during aging (3,13). Although the mechanism by which peripheral expansion occurs is not entirely elucidated, in vivo murine studies have pointed to low-affinity TCR binding as a potential inducer of naive T cell replication (14 -16), and in vitro human studies have found that IL-7 and various other cytokines can stimulate naive T cell division without loss of naive phenotype (17)(18)(19).…”

Cytokine Responses to Allergens during the First Two Years of Life in Estonian and Swedish Children

“…The T-cell receptors utilised by RTE are structurally different to those on mature naive or memory T-cells [28], and facilitate promiscuous low affinity reactions to a wide range of peptides, triggering an initial burst of cytokine production followed by rapid apoptosis, in some cases accompanied by bystander activation of regulatory T-cells [27]. As these RTE progressively die out during early childhood, they are presumably We believe that the responses are allergen specific, although the allergen extracts are not endotoxin free, since we have earlier reported that immune responses to birch extract are related to birch allergy [11] and that cells from birch or cat sensitised children respond with Th2 like cytokine production after stimulation with birch or cat allergen extract, but not after stimulation with an unrelated allergen [4].…”