title: Histone deacetylation critically determines T cell subset radiosensitivity.
abstract: 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.
authors.affiliation: Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724; Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85724; Graduate Interdisciplinary Program in Genetics, University of Arizona, Tucson, AZ 85719;
authors.forename: Jason L
authors.initials: JL
authors.lastname: Pugh
authors.affiliation: Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724; Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85724;
authors.forename: Alona S
authors.initials: AS
authors.lastname: Sukhina
authors.affiliation: Radiation Effects Research Foundation, Hiroshima 732-0815, Japan;
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Seed
authors.affiliation: Department of Genetics, University of Georgia, Athens, GA 30602;
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Manley
authors.affiliation: Department of Medicine, Duke University, Durham, NC 27710; Department of Pathology, Duke University, Durham, NC 27710; Duke Human Vaccine Institute, Duke University, Durham, NC 27710;
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Sempowski
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and.
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
authors.affiliation: Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724; Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85724;
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Smithey
authors.affiliation: Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724; Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85724; Graduate Interdisciplinary Program in Genetics, University of Arizona, Tucson, AZ 85719; BIO5 Institute, University of Arizona, Tucson, AZ 85719 nikolich@email.arizona.edu.
authors.forename: Janko
authors.initials: J
authors.lastname: Nikolich-Žugich
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000528:radiation effects; D002470:Cell Survival / Q000276:immunology / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004260:DNA Repair / Q000276:immunology / Q000528:radiation effects; D004306:Dose-Response Relationship, Immunologic; D004307:Dose-Response Relationship, Radiation; D056572:Histone Deacetylase Inhibitors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology / Q000528:radiation effects*
chemical_list: D056572:Histone Deacetylase Inhibitors