Apoptotic elimination of peripheral T lymphocytes in patients with primary intracranial tumors

Abstract

Patients with gliomas exhibit severe T lymphopenia during the course of the disease. This study was conducted to determine the mechanism(s) responsible for the lymphopenia. Using two-color fluorescent staining techniques, the authors show that significant numbers of T cells undergo apoptosis in the peripheral blood of patients with gliomas. To determine whether a glioma-derived factor(s) induces this apoptosis, rosette-purified T cells obtained from healthy donors were treated with glioma cell culture supernatant (GCCS) and examined for apoptosis. It is demonstrated that treatment of normal T cells with GCCS induced apoptosis only with concurrent stimulation of the T-cell receptor/CD3 complex. The addition of neutralizing antibodies to interleukin (IL)-10, IL-4, transforming growth factor alpha, or tumor necrosis factor-beta (lymphotoxin) did not rescue these T cells from apoptosis. Experiments were also conducted in which the degree of monocyte involvement in the induction of T-cell apoptosis was explored. The U937 cells were pretreated for 20 hours with a 1:20 dilution of GCCS. After the removal of GCCS, the U937 cells were cultured in transwell assays with stimulated T cells. Although control U937 cells did not induce apoptosis of the activated T cells, GCCS-pretreated U937 cells induced appreciable apoptosis in normal, stimulated T-cell cultures. These data indicate that one mechanism by which gliomas cause immunosuppressive effects is the induction of monocytes to release soluble factors that promote activated T-cell apoptosis. The loss of activated T cells leads to T lymphopenia and contributes to the deficiencies in cell-mediated immunity that have been observed during testing of glioma patients' immune function.