Abstract
Sublethal total body γ irradiation (TBI) of mammals causes generalized immunosuppression, in part by induction of lymphocyte apoptosis. Here, we provide evidence that a part of this immune suppression may be attributable to dysfunction of immune regulation. We investigated the effects of sublethal TBI on T cell memory responses to gain insight into the potential for loss of vaccine immunity following such exposure. We show that in mice primed to an MHC class I alloantigen, the accelerated graft rejection T memory response is specifically lost several weeks following TBI, whereas identically treated naïve mice at the same time point had completely recovered normal rejection kinetics. Depletion in vivo with anti-CD4 or anti-CD25 showed that the mechanism involved cells consistent with a regulatory T cell (T reg) phenotype. The loss of the T memory response following TBI was associated with a relative increase of CD4+CD25+ Foxp3+ expressing T regs, as compared to the CD8+ T effector cells requisite for skin graft rejection. The radiation-induced T memory suppression was shown to be antigen-specific in that a third party ipsilateral graft rejected with normal kinetics. Remarkably, following the eventual rejection of the first MHC class I disparate skin graft, the suppressive environment was maintained, with markedly prolonged survival of a second identical allograft. These findings have potential importance as regards the immunologic status of T memory responses in victims of ionizing radiation exposure and apoptosis-inducing therapies.
Highlights
Ionizing radiation exposure results in a range of DNA damage including strand breaks, base damage, and crosslinking, which in turn induces apoptosis in radiation sensitive tissues including lymphocytes [1]
The results indicate that CD8+ T cells are both necessary and sufficient to reject MHC class I disparate Dd skin allografts in naıve mice and for accelerated rejection in antigen primed mice
Ionizing Radiation-induced T Memory Suppression To evaluate the effects of ionizing radiation on memory T cell mediated allograft rejection responses, we evaluated the time to rejection of an MHC class I disparate skin graft in antigen primed mice, as well as in control naıve mice, at time points following sublethal irradiation
Summary
Ionizing radiation exposure results in a range of DNA damage including strand breaks, base damage, and crosslinking, which in turn induces apoptosis in radiation sensitive tissues including lymphocytes [1]. Limiting dilution analysis revealed a decrease within the CD4+ T cell population of individual CD4+ T cells able to proliferate in response to mitogens and IL-2 or to produce IL-2 [6]. This may have resulted from direct radiation-induced genetic damage as well as to generation of an imbalance in T reg vs T effector populations. The alterations in T cell populations observed in victims of ionizing radiation exposure, including increased memory and T reg subsets, have been described as similar to the effects of aging [13,1].
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