title: Acquired hematopoietic stem cell defects determine B-cell repertoire changes associated with aging.
abstract: Aging is associated with an inability to mount protective antibody responses to vaccines and infectious agents. This decline is associated with acquisition of defects in multiple cellular compartments, including B cells. While peripheral B-cell numbers do not decline with aging, the composition of the compartment appears to change, with loss of naïve follicular B cells, accumulation of antigen-experienced cells, and alteration of the antibody repertoire. The underlying cause of this change is unknown. We tested the hypothesis that aging-associated repertoire changes can be attributed directly to decreased B lymphopoiesis. Using an Ig transgenic model to report changes in the B-cell repertoire, we show that the reduced B-cell generative capacity of "aged" long-term reconstituting hematopoietic stem cells (LT-HSCs) alters the representation of antigen specificities in the peripheral B-cell repertoire. Further, we show that reconstitution using suboptimal numbers of fully functional LT-HSCs results in the generation of a similarly altered B-cell repertoire. This may be an important factor to consider when deciding the number of bone marrow cells to transplant in the clinical setting. In conclusion, when B lymphopoiesis is limited peripheral B-cell homeostasis is altered. This is reflected in reduced diversity of the B-cell repertoire, which likely reduces the protective quality of the immune response.
authors.affiliation: Department of Immunology, University of Colorado, Denver School of Medicine and National Jewish Health, Denver, CO 80206, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Guerrettaz
authors.forename: Sara A
authors.initials: SA
authors.lastname: Johnson
authors.forename: John C
authors.initials: JC
authors.lastname: Cambier
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology*; D038041:Lymphopoiesis; D051379:Mice