T Cells Are the Cellular Target of the Proliferation-Augmenting Effect of Chronic Low-Dose Ionizing Radiation in Mice

Abstract

The proliferative response to mitogenic stimulation by splenocytes can be augmented by exposing mice to whole-body, chronic, intermittent low doses of ionizing radiation, referred to here as low-dose irradiation. The purpose of this study was to identify the cell(s) in the spleen which is responsive to the proliferation-augmenting effect of low-dose irradiation, i.e., the cellular target. C57BL/6 mice were subjected to low-dose irradiation (0.04 Gy/exposure/day, 5 consecutive days/week, 2 weeks) or to sham irradiation. Three days after the last exposure, spleens were removed, separated into cell fractions which were nonadherent and adherent to plastic surfaces and reconstituted in various combinations, and their proliferative responses to various mitogens were determined. Highly purified T cells were also used in place of the nonadherent cell fraction in the reconstitution studies. The target cells were shown to be T cells. The target T cells of low-dose-irradiated mice possessed elevated constitutive levels of HSP-70 mRNA and HSP-72, and they responded to T-cell receptor-specific anti-CD3 stimulation by producing more HSP-70 mRNA and HSP-72 and by proliferating more extensively than T cells of sham-irradiated mice.

Identification of radiation-specific responses from gene expression profile

“…IR works via DNA damage and reactive oxygen species (ROS) generation, which can induce the transcription of specific genes through the activation of p53, NF-kB and AP-1 (Liu et al, 1996;Khanna and Jackson, 2001;Lu-Hesselmann et al, 1997;Nogami et al, 1994;Safwat, 2000). Although p53 will play the most important role in cellular response to ionizing radiation, the other pathways through AP-1 and NFkB will also participate in a p53-independent way (Wahl and Carr, 2001).…”

Enhancement of T Cell Responses as a Result of Synergy between Lower Doses of Radiation and T Cell Stimulation

“…RT has two well-known immunological links, as follows: one is the need for properly functioning host cellular immune system, especially CD8 + T cells, for maximum benefit from RT (1,2); the second is the much discussed abscopal effect (regression of distant disease following local irradiation) that, in preclinical models (3,4), was proved to be immune mediated. Generally, tumors are treated with a single high dose (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Gy) or multiple fractions of ∼2 Gy radiation, amounting to 60-70 Gy total dose. High-dose RT can provide tumor Ags from dying cells for dendritic cells that then cross-present them to CD8 + T cells.…”

“…Positive effects on T cell function may be induced in a nonlinear manner by lower radiation doses, but information is scarce. Nogami et al (16) observed enhanced TCR stimulation-induced T cell proliferation in mice receiving low-dose total body irradiation, but no mechanistic study was conducted. We have found increased IFN-g release by human T cells to viral recall peptides in PBMC irradiated in vitro with 0.6-2.4 Gy (17), an observation that formed the basis of the hypothesis for the work presented in this study.…”

Changes in the Activation and Reconstitution of Lymphocytes Resulting from Total-Body Irradiation Correlate with Slowed Tumor Growth

“…While numerous experiments have documented the immunosuppressive effect of high-dose total-body irradiation (TBI) [1, 2], mounting evidence suggests that an augmentation of certain immune parameters can be achieved when TBI is given in low doses [3, 4]. Current therapeutic regimens for low-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia, which have resulted in long-term remission in some patients, include treatment schedules that prescribe a total cumulative dose between 1.5 and 2.0 Gy [5, 6].…”

“…An upregulation of interferon-γ and tumor necrosis factor-α mRNA combined with a decrease in transforming growth factor (TGF)-β expression by splenocytes were also noted. Other studies have reported that T cells are responsive to low-dose irradiation and can proliferate more extensively than B cells [4]. Furthermore, splenic and thymic lymphocyte proliferation induced by TBI are potentially mediated through signal transduction within these cells [8, 9].…”