Age-associated B cells (ABC) inhibit B lymphopoiesis and alter antibody repertoires in old age

Abstract

With old age (∼2y old), mice show substantial differences in B cell composition within the lymphoid tissues. In particular, a novel subset of IgM+ CD21/35lo/− CD23− mature B cells, the age-associated B cells or ABC, increases numerically and proportionately. This occurs at the expense of other B cell subsets, including B2 follicular B cells in spleen and recirculating primary B cells in bone marrow. Our studies suggest that ABC have a distinctive antibody repertoire, as evidenced by relatively high reactivity to the self-antigens phosphorylcholine (PC) and malondialdehyde (MDA). While PC and MDA are found on apoptotic cells and oxidized lipoproteins, antibodies to these antigens are also cross-reactive with epitopes on bacterial species. In old mice, ABC express TNFα and are pro-inflammatory. ABC can inhibit growth and/or survival in pro-B cells as well as common lymphoid progenitors (CLP). In particular, ABC cause apoptosis in pro-B cells with relatively high levels of the surrogate light chain (SLC) and, consequently, promote an “SLC low” pathway of B cell differentiation in old mice. SLC together with μ heavy chain comprises the pre-B cell receptor (preBCR) critical for pre-B cell expansion and selection of the μ heavy chain Vh repertoire. The low level of SLC likely impairs normal preBCR driven proliferation and alters μ heavy chain Vh selection thereby affecting the antibody specificities of new B cells. In this manner, ABC may contribute to both qualitative and quantitative disruptions of normal B lymphopoiesis in old age.