Histone Deacetylation Critically Determines T Cell Subset Radiosensitivity

Abstract

Lymphocytes are sensitive to ionizing radiation and naïve lymphocytes are more radiosensitive than their memory counterparts. Less is known about radiosensitivity of memory cell subsets. We examined the radiosensitivity of naïve (TN), effector memory (TEM), and central memory (TCM) T cell subsets in C57BL/6 mice, and found TEM to be more resistant to radiation-induced apoptosis than either TN or TCM. Surprisingly, we found no correlation between the extent of radiation-induced apoptosis in T cell subsets and : (i) levels of pro- and anti-apoptotic Bcl-2 family members; or (ii) the H2-AX content and maximal γH2-AX fold change. Rather, TEM cell survival correlated with higher levels of immediate γH2-AX marking, immediate break binding and genome-wide open chromatin structure. T cells were able to mark DNA damage seemingly instantly (30 s), even if kept on ice. Relaxing chromatin with the histone deacetylase inhibitor valproic acid following radiation or etoposide treatment, improved the survival of TCM and TN cells up to levels seen in the resistant TEM cells, but did not improve survival from caspase-mediated apoptosis. We conclude that an open genome-wide chromatin state is the key determinant of efficient immediate repair of DNA damage in T cells, explaining the observed T cell subset radiosensitivity differences.

Radiation Sensitivity of Human CD34+Cells Versus Peripheral Blood T Lymphocytes of Newborns and Adults: DNA Repair and Mutagenic Effects

“…According to our findings, the observed differences in foci 24 h postirradiation and micronuclei yields between newborn and adult T lymphocytes are related to the immunophenotypic changes in T-lymphocyte composition with respect to naive and memory subsets. In agreement with our findings, studies in murine models could also show that naive lymphocytes are more radiosensitive than their memory counterparts (57)(58)(59). Up to now, the underlying mechanisms of the observed difference in radiosensitivity of human naive and memory T-lymphocyte subsets remains an open question and future research is warranted.…”

“…The memory CD4 þ T-cell subset in infants and young children has a significantly higher ratio of central memory to effector memory CD4 T cells than in adults (69). The murine study of Pugh et al demonstrated a difference in radiosensitivity between these memory subsets, which was again linked to their chromatin state (57). Although no statistically significant difference could be observed in residual foci and micronuclei levels of newborn and adult memory CD4 þ subsets, the P values were less convincing (P ¼ 0.150) than those we obtained for the naive cells and this can probably be attributed to the T lymphocyte central to effector memory cell ratio.…”

Opportunities and challenges of radiotherapy for treating cancer

“…54,59 Also, chromatin structure varies with cell activity and status, and this variation is a suggested explanation for observed differences in radiosensitivity between T-cell subsets. 60 In the longer term, greater understanding of the dynamics of RIF viz-a-viz chromatin structure should give rise to new biomarkers of radiosensitivity and identify novel therapeutic targets.…”

CD4+ memory T cells retain surface expression of CD31 independently of thymic function in patients with lymphoproliferative disorders following autologous hematopoietic stem-cell transplantation

“…Interestingly, we showed a slight depletion of RTEs in patients after local non-mediastinal RT. Such effect after peripheral local irradiation was also described by several authors [15,19] and may be explained by higher sensitivity of naïve T cells to RT compared with memory T-cells [20]. Yovino et al recently demonstrated that 61.5% of the blood pool received more than 0.5 Gy after local irradiation in total dose of 20 Gy [19], wherein the dose required to reduce the surviving fraction of T cells to 50% is about 2 Gy [21].…”