Impact of whole-body radiation exposure on pathogen-specific memory CD8 T cells

About This Grant

Accidental or deliberate radiation exposure of humans remains a major health concern, due to the paucity of medical countermeasures (MCMs) to ameliorate radiation-induced damage. While high dose radiation exposure is generally fatal, even low dose whole body (WBI) or partial radiation exposure can have acute- and/or delayed- negative impacts that appear to act through disruption of the immune system. The cytoreductive effects of WBI have long been exploited in conjunction with chemotherapy as a preparative regimen prior to hematopoietic stem cell transplant in patients with blood cancer to deplete malignant cells and suppress the immune system. While there is strong evidence that radiation kills rapidly dividing cells, a hallmark of the immune system, and induces inflammation that can mediate tissue destruction, the precise nature of radiation induced immune-dysfunction is not well understood. This knowledge gap is a key impediment to development of MCMs to treat radiation exposure. For one example, memory CD8 T cells provide enhanced resistance to re-infection and malignancies. However, most studies in the literature examine the impact of radiation exposure on the capacity of the host’s naïve CD8 T cells to mount a new (primary) immune response and just a few reports have looked at how radiation exposure influences the longevity and protective capacity of pre-existing pathogen or vaccine-induced CD8 T cell memory. Memory CD8 T cell populations have the job of surveying the entire body for signs of re-infection. They accomplish this task using two complimentary and interactive strategies. This first strategy involves populations of memory CD8 T cells that survey the body by using the circulatory system (circulating memory CD8 T cells - Tcircm). The second strategy involves the generation of a population of non-circulating memory CD8 T cells (called T resident memory, Trm), generally in the tissue of pathogen entry. These cells, which persist long-term in tissues, provide rapid detection of re-invading pathogens and then send out mediators to recruit other cells of the immune system to the site of infection. Importantly, our recent data obtained after WBI or partial (targeted) thorax radiation suggest that sublethal ionizing radiation inflicted numerical and functional damage to Tcircm and Trm cells that diminished their ability to provide protection to pathogen-re-encounter. Our long-term goal is to precisely identify mechanisms that govern maintenance, differentiation and function of infection and/or vaccine- induced memory CD8 T cell subsets and explore modalities to recover memory CD8 T cell responses in radiation survivors. We will address our long-term goal through the following specific aims: SA1 - Delineate the tissue-specific impact of WBI on pathogen-specific Trm and evaluate targeted vaccine strategies to restore memory CD8 T cell numbers and function after irradiation. SA 2 - Define mechanisms underlying WBI-induced numerical and functional diminishment of Tcircm and exhausted (Tex) CD8 T cells generated after acute or chronic viral infections.