title: Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity.
abstract: Although the accumulation of highly-differentiated and granzyme B (GrB)-expressing CD8(+)CD28(-) T cells has been associated with aging, the mechanism for their enrichment and contribution to immune function remains poorly understood. Here we report a novel B-cell subset expressing 4-1BBL, which increases with age in humans, rhesus macaques, and mice, and with immune reconstitution after chemotherapy and autologous progenitor cell transplantation. These cells (termed 4BL cells) induce GrB(+)CD8(+) T cells by presenting endogenous antigens and using the 4-1BBL/4-1BB axis. We found that the 4BL cells increase antitumor responses in old mice, which may explain in part the paradox of retarded tumor growth in the elderly. 4BL cell accumulation and its capacity to evoke the generation of GrB(+)CD8(+) T cells can be eliminated by inducing reconstitution of B cells in old mice, suggesting that the age-associated skewed cellular immune responses are reversible. We propose that 4BL cells and the 4-1BBL signaling pathway are useful targets for improved effectiveness of natural antitumor defenses and therapeutic immune manipulations in the elderly.
authors.affiliation: Immunoregulation Section, Laboratory of Molecular Biology and Immunology, Baltimore, MD;
authors.forename: Catalina
authors.initials: C
authors.lastname: Lee-Chang
authors.affiliation: Immunoregulation Section, Laboratory of Molecular Biology and Immunology, Baltimore, MD;
authors.forename: Monica
authors.initials: M
authors.lastname: Bodogai
authors.affiliation: Immunoregulation Section, Laboratory of Molecular Biology and Immunology, Baltimore, MD;
authors.forename: Kanako
authors.initials: K
authors.lastname: Moritoh
authors.affiliation: Immunoregulation Section, Laboratory of Molecular Biology and Immunology, Baltimore, MD;
authors.forename: Purevdorj B
authors.initials: PB
authors.lastname: Olkhanud
authors.affiliation: Department of Immunology, Genentech, Inc., South San Francisco, CA;
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Chan
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA;
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.affiliation: The Nonhuman Primate Core Facility, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD;
authors.forename: Julie A
authors.initials: JA
authors.lastname: Mattison
authors.affiliation: Laboratory of Experimental Vaccinology, Department of International Health, Immunology and Microbiology, University of Copenhagen, Denmark;
authors.forename: Peter Johannes
authors.initials: PJ
authors.lastname: Holst
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD; and.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gress
authors.affiliation: Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD; and.
authors.forename: Fran
authors.initials: F
authors.lastname: Hakim
authors.affiliation: Immunoregulation Section, Laboratory of Molecular Biology and Immunology, Baltimore, MD;
authors.forename: Arya
authors.initials: A
authors.lastname: Biragyn
mesh_terms: D053330:4-1BB Ligand / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D005260:Female; D053804:Granzymes / Q000378:metabolism*; D006801:Humans; D007111:Immunity, Cellular; D007113:Immunity, Innate; D008253:Macaca mulatta; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D015398:Signal Transduction; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000378:metabolism
chemical_list: D053330:4-1BB Ligand; C505974:TNFSF9 protein, human; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse