title: Age-Associated B Cells Express a Diverse Repertoire of VHand Vκ Genes with Somatic Hypermutation.
abstract: The origin and nature of age-associated B cells (ABCs) in mice are poorly understood. In this article, we show that their emergence required MHC class II and CD40/CD40L interactions. Young donor B cells were adoptively transferred into congenic recipients and allowed to remain for 1 mo in the absence of external Ag. B cells expressing the T-bet transcription factor, a marker for ABCs, were generated after multiple cell divisions from C57BL/6 donors but not from MHC class II- or CD40-deficient donors. Furthermore, old CD154 (CD40L)-deficient mice did not accrue ABCs, confirming that they arise primarily through T-dependent interactions. To determine what Igs ABCs express, we sequenced VHand Vκ rearranged genes from unimmunized 22-mo-old C57BL/6 mice and showed that they had a heterogeneous repertoire, which was comparable to that seen in old follicular and marginal zone B cell subsets. However, in contrast to the follicular and marginal zone cells, ABCs displayed significant somatic hypermutation. The mutation frequency was lower than found in germinal center cells after deliberate immunization, suggesting that ABCs have undergone mild stimulation from endogenous Ags over time. These observations show that quiescent ABCs are Ag-experienced cells that accumulate during T cell-dependent responses to diverse Ags during the life of an individual.
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Russell Knode
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Martin S
authors.identifier: 0000-0003-1926-0382
authors.initials: MS
authors.lastname: Naradikian
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Arpita
authors.initials: A
authors.lastname: Myles
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Scholz
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Emory Transplant Center and Department of Surgery, Emory University, Atlanta, GA 30322; and.
authors.forename: Danya
authors.identifier: 0000-0001-6103-6486
authors.initials: D
authors.lastname: Liu
authors.affiliation: Emory Transplant Center and Department of Surgery, Emory University, Atlanta, GA 30322; and.
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
authors.affiliation: Penn Molecular Profiling Facility, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: John W
authors.identifier: 0000-0002-5362-7013
authors.initials: JW
authors.lastname: Tobias
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; cancro@mail.med.upenn.edu gearhartp@mail.nih.gov.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cancro
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; cancro@mail.med.upenn.edu gearhartp@mail.nih.gov.
authors.forename: Patricia J
authors.identifier: 0000-0003-1975-4737
authors.initials: PJ
authors.lastname: Gearhart
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000172:deficiency / Q000276:immunology; D015321:Gene Rearrangement; D005802:Genes, MHC Class II; D018858:Germinal Center / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D017422:Sequence Analysis, DNA; D061905:Single-Domain Antibodies / Q000235:genetics*; D027041:Somatic Hypermutation, Immunoglobulin
chemical_list: D019013:CD40 Antigens; D061905:Single-Domain Antibodies