title: Aging Converts Innate B1a Cells into Potent CD8+ T Cell Inducers.
abstract: B cell dysregulation in aging is thought to mostly occur in conventional B2 cells without affecting innate B1 cells. Elderly humans and mice also accumulate 4-1BBL(+)MHC class-I(Hi)CD86(Hi)B cells of unknown origin. In this article, we report that these cells, termed 4BL cells, are activated murine and possibly human B1a cells. The activation is mediated by aging human monocytes and murine peritoneal macrophages. They induce expression and activation of 4-1BBL and IFN-γR1 on B1a cells to subsequently upregulate membrane TNF-α and CD86. As a result, activated B1a/4BL cells induce expression of granzyme B in CD8(+)T cells by targeting TNFR2 via membrane TNF-α and providing costimulation with CD86. Thus, for the first time, to our knowledge, these results indicate that aging affects the function of B1a cells. Upon aging, these cells lose their tumor-supporting activity and become inducers of potentially antitumor and autoimmune CD8(+)T cells.
authors.affiliation: Immunoregulation Section, National Institute on Aging, Baltimore, MD 21224; INSERM UMR995, Lille Inflammation Research International Center, F-59000 Lille, France; University of Lille, F-59000 Lille, France;
authors.forename: Catalina
authors.identifier: http://orcid.org/0000-0002-7675-2124
authors.initials: C
authors.lastname: Lee-Chang
authors.affiliation: Immunoregulation Section, National Institute on Aging, Baltimore, MD 21224;
authors.forename: Monica
authors.identifier: http://orcid.org/0000-0002-8174-9608
authors.initials: M
authors.lastname: Bodogai
authors.affiliation: Immunoregulation Section, National Institute on Aging, Baltimore, MD 21224;
authors.forename: Kanako
authors.identifier: http://orcid.org/0000-0001-7501-6806
authors.initials: K
authors.lastname: Moritoh
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao Special Administrative Region, People's Republic of China; Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702;
authors.forename: Xin
authors.identifier: http://orcid.org/0000-0002-2628-4027
authors.initials: X
authors.lastname: Chen
authors.affiliation: Flow Cytometry Unit, National Institute on Aging, Baltimore, MD 21244;
authors.forename: Robert
authors.initials: R
authors.lastname: Wersto
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD 21224;
authors.forename: Ranjan
authors.initials: R
authors.lastname: Sen
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702;
authors.forename: Howard A
authors.identifier: http://orcid.org/0000-0002-3118-5111
authors.initials: HA
authors.lastname: Young
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.affiliation: Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: Immunoregulation Section, National Institute on Aging, Baltimore, MD 21224; biragyna@mail.nih.gov.
authors.forename: Arya
authors.identifier: http://orcid.org/0000-0001-5276-6102
authors.initials: A
authors.lastname: Biragyn
mesh_terms: D053330:4-1BB Ligand / Q000378:metabolism; D000328:Adult; D000368:Aged; D000375:Aging / Q000276:immunology*; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002478:Cells, Cultured; D016922:Cellular Senescence; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D053804:Granzymes / Q000096:biosynthesis; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D053330:4-1BB Ligand; D051940:B7-2 Antigen; D053804:Granzymes; D015395:Histocompatibility Antigens Class I; D017471:Receptors, Interferon; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C509214:Gzmb protein, mouse