title: Rescue of CD8+ T cell vaccine memory following sublethal γ irradiation.
abstract: Sublethal γ irradiation eliminates CD8+ T cell mediated memory responses. In this work, we explored how these memory responses could be rescued in the aftermath of such exposure. We utilized two models of CD8+ T cell mediated immunity: a mouse model of Listeria monocytogenes (LM) infection in which CD8+ T cells specific for LM expressed antigens (Listeriolysin O, LLO) can be tracked, and a murine skin graft model in which CD8+ T cells mediate rejection across a MHC class I (D(d)) disparity. In the LM immunized mice, LL0 specific CD8+ T memory cells were lost on irradiation, preserved with rapid revaccination with an attenuated strain 1-3 days post-irradiation (PI), and these mice survived a subsequent wild type LM challenge. A genetic "signature of rescue" identified a group of immune-associated mRNA maintained or upregulated following irradiation and rescue. A number of these factors, including IL-36γ, dectin-2 (Clec4n), and mir101c are upregulated rapidly after exposure of mice to sublethal γ radiation alone and are sustained by early, but not later rescue. Such factors will be evaluated as potential therapeutics to replace individual vaccines for global rescue of CD8+ T memory cell responses following sublethal γ irradiation. The skin allograft model mirrored that of the LM model in that the accelerated D(d) skin allograft rejection response was lost in mice exposed to sublethal γ radiation, but infusion of allogeneic D(d) expressing bone marrow cells 1-4 days PI preserved the CD8+ T memory mediated accelerated rejection response, further suggesting that innate immune responses may not always be essential to rescue of CD8+ memory T cells following γ irradiation.
authors.affiliation: Division of Research and Review 3, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA. Electronic address: hugh.mcfarland@fda.hhs.gov.
authors.forename: Hugh I
authors.initials: HI
authors.lastname: McFarland
authors.affiliation: Division of Research and Review 3, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA. Electronic address: julia.berkson@fda.hhs.gov.
authors.forename: Julia D
authors.initials: JD
authors.lastname: Berkson
authors.affiliation: Division of Research and Review 3, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA; George Washington School of Medicine and Health Sciences, Ross Hall, 2300 Eye St. NW, Washington, DC 20037, USA. Electronic address: jlee17@gwmail.gwu.edu.
authors.forename: Jay P
authors.initials: JP
authors.lastname: Lee
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, 50 South Dr., Bethesda, MD 20892, USA. Electronic address: abdel@nhgri.nih.gov.
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.affiliation: Division of Research and Review 3, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA; Intramural Administrative Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 5640 Fishers Ln., Rockville, MD 20892, USA. Electronic address: karen.mason2@nih.gov.
authors.forename: Karen P
authors.initials: KP
authors.lastname: Mason
authors.affiliation: Division of Research and Review 3, Office of Biotechnology Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993, USA. Electronic address: amy.rosenberg@fda.hhs.gov.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Rosenberg
mesh_terms: D064591:Allografts / Q000276:immunology; D000818:Animals; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005720:Gamma Rays; D006084:Graft Rejection; D007156:Immunologic Memory; D008089:Listeria monocytogenes / Q000276:immunology; D008807:Mice, Inbred BALB C; D000069079:Radiation Exposure
chemical_list: D001428:Bacterial Vaccines