Histone Deacetylation Critically Determines T Cell Subset Radiosensitivity

Lymphocytes are sensitive to ionizing radiation and naive lymphocytes are more radiosensitive than their memory counterparts. Less is known about radiosensitivity of memory cell subsets. We examined the radiosensitivity of naive (T-N), effector memory (T-EM), and central memory (T-CM) T cell subsets in C57BL/6 mice and found T-EM to be more resistant to radiation-induced apoptosis than either T-N or T-CM. Surprisingly, we found no correlation between the extent of radiation-induced apoptosis in T cell subsets and 1) levels of pro- and antiapoptotic Bcl-2 family members or 2) the H2AX content and maximal gamma H2AX fold change. Rather, T-EM cell survival correlated with higher levels of immediate gamma H2AX 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 T-CM and T-N cells up to levels seen in the resistant T-EM 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.