Abstract
Senescent mice show diminished B lymphopoiesis as well as alterations in mature B cell compartments. Within both spleen and bone marrow (BM), aged mice show ~5-10 fold increases in "age associated B cells (ABC)", which is a normally minor mature B cell subset that lacks surface expression of CD21/35 and CD23. This population, through senescence acquired secretion of TNF-alpha, can induce apoptosis in pro-B cells directly, as well as indirectly through the bone marrow. Adoptive transfer experiments suggest ABC contribute to a pro-inflammatory environment within the bone marrow of aged mice. Old FO and FO-like BM B cells produce TNFà while young do not, but both ages contain an IL-10 producing subset, which can abrogate the effects of TNFà on pro-B cells. The increased ABC relative to the FO-like B cells in the bone marrow showed significant correlation to the loss of B cell recursors (BCP) in old mice in vivo. This in turn contributes to the loss in B lymphopoiesis seen in old age. Aged pre-B and pro-B cells have reduced expression of the surrogate light chain (SLC; VpreB, Lambda5), part of the pre-BCR complex. In both aged mice and ABC adoptive transfer recipients, pro-B cells show decreased expression of SLC. BCP that show little or no SLC expression are resistant to TNFà induced apoptosis. Pro-B cells express a "pro-BCR?" complex that contains cadherin 17 (cadh17) and SLC. Low expression of cadh17/SLC in pro-B cells is associated with increased phosphorylation of pro-apoptotic Bim, leading to its inactivation and degradation. Crosslinking cadh17 on the surface of SLClo pro-B cells restores apoptotic sensitivity to TNF-alpha by reducing the levels of phospho-Bim. Loss of SLC also alters the susceptibility of pro-B cells to a very different apoptotic stimulus, TGF?, at the signal transduction and nuclear translocation stages. These results suggest that alterations in B cell composition in old age contribute to an inflammatory bone marrow microenvironment, which preferentially targets pro-B cells that express high levels of SLC, inducing apoptosis and reducing the pool of pro-B cells in aged mice to low SLC expressing cells. This loss of high SLC expressing pro-B cells likely compromises B cell development at the pro-B to pre-B transition.