TY - JOUR
T1 - Histone deacetylation critically determines T cell subset radiosensitivity
AU - Pugh, Jason L.
AU - Sukhina, Alona S.
AU - SeedG, Thomas M.
AU - Manley, Nancy R.
AU - Sempowski, Gregory D.
AU - Van Den Brink, Marcel R.M.
AU - Smithey, Megan J.
AU - Nikolich-Žugich, Janko
PY - 2014/8/1
Y1 - 2014/8/1
N2 - 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 (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 1) levels of pro-and antiapoptotic Bcl-2 family members or 2) the H2AX content and maximal γH2AX fold change. Rather, TEM cell survival correlated with higher levels of immediate γH2AX 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.
AB - 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 (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 1) levels of pro-and antiapoptotic Bcl-2 family members or 2) the H2AX content and maximal γH2AX fold change. Rather, TEM cell survival correlated with higher levels of immediate γH2AX 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.
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U2 - 10.4049/jimmunol.1400434
DO - 10.4049/jimmunol.1400434
M3 - Article
C2 - 24990082
AN - SCOPUS:84906079463
VL - 193
SP - 1451
EP - 1458
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 3
ER -