Ionizing radiation effects on MHC class I antigen presentation

Radiation is generally considered to be an immunosuppressive agent that acts by killing radiosensitive lymphocytes. In this study, we demonstrate additional noncytotoxic effects of ionizing radiation on MHC class I antigen presentation by bone marrow-derived dendritic cells (DCs) that have divergent consequences depending upon whether peptides are endogenously processed and loaded onto MHC class I molecules or are added exogenously. The endogenous pathway was examined using C57BL/6 murine DCs transduced with adenovirus (AdVMART1) to express the human MART-1 melanoma/melanocyte antigen. Prior irradiation abrogated the ability of AdVMART1-transduced DCs to induce MART-1 specific T cell responses following their injection into mice. Not only did irradiated DCs fail to generate a response but they were able to prevent and switch off a normal immune response to AdVMART1/DC stimulation. The ability of these same DCs to generate protective immunity against growth of B16 melanoma tumors, which expresses murine MART-1, was also abrogated by radiation. In addition to in vitro radiation effects on DC, in vivo irradiation not only inhibited tumor immunity and blocked its generation, possibly through induction of immune tolerance.; Failure of AdVMART1-transduced DCs to generate anti-tumor immunity following irradiation was not due to cytotoxicity or to radiation-induced block in DC maturation or loss in expression of MHC class I or co-stimulatory molecules. Some of these processes were affected, but since irradiation actually enhanced the ability of DCs to generate lymphocyte responses to the HLA-A2 epitope MART-127-35, these were unlikely to be critical. The increase in lymphocyte responses generated by irradiated DCs pulsed with MART-1 27-35 also protected mice against growth of B16-A2/Kb melanoma tumors in HLA-A2.1/Kb transgenic mice.; Taken together, these results suggest that irradiation modulates MHC class I-mediated anti-tumor immunity by functionally affecting DC antigen processing and presentation pathways. This effect of ionizing radiation on DC function to generate immunity MART-1 suggests a novel mechanism of radiation-induced immunosuppression and is possibly exerted through radiation-induced proteasome inhibition.